Fatty acid acetylated salicylates and their uses

ABSTRACT

The invention relates to Fatty Acid Acetylated Salicylate Derivatives; compositions comprising an effective amount of a Fatty Acid Acetylated Salicylate Derivative; and methods for treating or preventing an inflammatory disorder comprising the administration of an effective amount of a Fatty Acid Acetylated Salicylate Derivative.

1. PRIORITY

This application is a continuation of U.S. patent application Ser. No.13/427,639 filed Mar. 22, 2012, which claims the benefit of U.S. patentapplication Ser. No. 12/499,779 filed Jul. 8, 2009, which claims thebenefit of U.S. Provisional Application No. 61/148,658, filed Jan. 30,2009, U.S. Provisional Application No. 61/104,363, filed Oct. 10, 2008,U.S. Provisional Application No. 61/104,364, filed Oct. 10, 2008, U.S.Provisional Application No. 61/104,366, filed Oct. 10, 2008, and U.S.Provisional Application No. 61/078,983, filed Jul. 8, 2008. The entiredisclosures of those applications are relied on and incorporated intothis application by reference.

2. FIELD OF THE INVENTION

The invention relates to Fatty Acid Acetylated Salicylate Derivatives,Fatty Acid Acetylated Diflunisal Derivatives, and Fatty Acid AcetylatedTriflusal Derivatives (“Compounds of the Invention”); compositionscomprising an effective amount of a Fatty Acid Acetylated SalicylateDerivative, a Fatty Acid Acetylated Diflunisal Derivative, and/or aFatty Acid Acetylated Triflusal Derivative (“Compound of theInvention”); and methods for treating or preventing an inflammatorydisease comprising the administration of an effective amount of aCompound of the invention. All patents, patent applications andpublications cited herein are hereby incorporated by reference in theirentireties.

3. BACKGROUND OF THE INVENTION

Inflammatory pathways underlie the key pathophysiology of many chronicand acute diseases. Unresolved inflammation is important in many chronicdisorders, including, but not limited to, heart disease,atherosclerosis, type 1 and type 2 diabetes, dyslipidemia, asthma,arthritis (including rheumatoid arthritis (RA)), osteoarthritis, cysticfibrosis, muscle wasting disease (including muscular dystrophy), pain,insulin resistance, oxidative stress, inflammatory bowel disease (IBD)(including colitis and Crohn's disease), and neurodegenerative disease(including Alzheimer's disease).

In more recent years, the study of inflammation has gone deeper into thecell. Cell-signaling molecules have been identified that modulate theexpression of genes that control the inflammatory response, includingthe pro-inflammatory response and the anti-inflammatory response. One ofthe central regulators that balance the genes encoding anti- andpro-inflammation factors is Nuclear Factor Kappa Beta (NFκB). NFκB is afamily of transcriptions factors that include p50 (NFκB1), p52 (NFκB2),p65 (RelA), c-Rel and RelB. These nuclear factors are held as complexesor dimeric pairs in an inactive state in the cytoplasm as a complex by aNFκB inhibitory factor IκB. The IκB proteins include IκBα, IκBβ, andIκBε, but others also exist. The inactive NFκB complex is released fromthe cytoplasm by phosphorylation of the IκB protein through kinases suchas IKKβ. The kinases regulating NFκB activity are activated by immuneresponses or cellular stresses. Thus, in the cytoplasmic NFκB complexsuch as IkB/p65/p50, IkB becomes phosphorylated through kinases such asIKKβ and releases dimeric pairs of NFκB to the nucleus such as p65/p50.In the nucleus, NFκB regulates genetic expression of proinflammatoryfactors such as cytokines like TNFα, IL-6, and IL-1β in addition toenzymes such as cyclooxygenase-2 (COX-2) one of the enzymes thatconverts arachidonic acid to prostaglandin H2 (PGH2). These factorsinduce inflammation in various tissues. In addition, depending upon thecellular context and the NFκB nuclear factors released NFκB can causethe expression of anti-inflammatory genes.

Salicylates and other non-steroidal anti-inflammatory drugs (NSAIDs) caninfluence the NFκB pathway, allowing people to derive relief and reducedinflammation from these drugs. Aspirin and COX inhibitors act to reduceinflammation by reversibly or irreversibly blocking access to thehydrophobic channel via acetylation of serine 530 (COX-1) or Serine 516(COX-2). For some selective NSAIDs with a carboxylate group, there issignificant charge-charge interaction with Arginine 120. This binding orinteraction blocks the cyclooxygenase enzyme that forms PGH₂. Salicylatedoes not irreversibly inhibit cyclooxygenase because it lacks theability to acylate the COX enzyme and has little, if any, directinhibitory action on the COX enzyme at concentrations that are relevantin vivo. Salicylate has been shown to inhibit the activity of IKKβ andthereby inhibit NFκB leading to reduced expression of COX-2 in aninflammatory state where COX-2 expression has been induced.

Another example of an NSAID is diflunisal:

Yet another example of an NSAID is triflusal:

Diflunisal and Triflusal are commonly used to relieve pain, tenderness,swelling and stiffness caused by osteoarthritis and rheumatoidarthritis, and to relieve mild to moderate ain generally.

Problems arise in salicylate therapy due to side effects, which meansalternative ways need to be developed and pursued to reduce NFκBactivity. Some salicylates, when given orally, have a key disadvantageof causing gastric ulcers over the long term in chronic administration.In addition, salicylates can be strong irritants, thought to be causedby the high local concentration of these COX inhibitors. Many of theunwanted effects of aspirin are caused by the inappropriate inhibitionof COX or the NFκB pathway. Although NSAIDs inhibit COX and areefficacious anti-inflammatory agents, adverse effects limit their use.

Other anti-inflammatory agents that modulate NFκB activity are omega-3polyunsaturated fatty acids (PUFA). Omega-3 fatty acids also reduceIL-1, which is an activator of NFκB, and increase anti-inflammatorycytokines, such as IL-10, and adipokines, such as adiponectin. Oily coldwater fish, such as salmon, trout, herring, and tuna are the source ofdietary marine omega-3 fatty acids with eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA) being the key marine derived omega-3 fattyacids. Leafy green vegetables, and certain beans, nuts or oils, such assoybeans, walnuts, flaxseed, and canola oil, are also rich dietarysources of omega-3 fatty acids.

The anti-inflammatory effects of omega-3 fatty acids have been widelystudied with positive results for several chronic inflammatory diseases.TNFα and IL-6 are cytokines that increase dramatically duringinflammatory processes and are commonly measured as markers ofinflammation. Greater intake of omega-3 PUFA has been shown to associatestrongly with lower levels of circulating TNFα and IL-6 (Ferrucci etal., 2006). Furthermore, higher intake of omega-3 PUFA has also beenassociated with increased levels of markers of anttinflammation,including the well-characterized anti-inflammatory cytokine IL-10(Ferruccci et al, 2006). Animal models of colitis indicate that fish oildecreases colonic damage and inflammation, weight loss, and mortality.Fish oil supplements in patients with IBD have shown to modulate levelsof inflammatory mediators and may be beneficial for the induction andmaintenance of remission in ulcerative colitis.

In the management of RA and other inflammatory conditions, side effectslimit the use of NSAIDs. A clinical trial showed that 39 percent ofpatients with RA supplemented with cod liver oil were able to reducetheir daily NSAID requirement by greater than 30 percent. Omega-3 fattyacids have been used to reduce the risk for sudden death caused bycardiac arrhythmias, have been taken as dietary supplements and theethyl ester of omega-3 fatty acids as a combination therapy is used totreat dyslipidemia.

Furthermore, omega-3 fatty acids have been shown to improve insulinsensitivity and glucose tolerance in normoglycemic men and in obeseindividuals. Omega-3 fatty acids have also been shown to improve insulinresistance in obese and non-obese patients with an inflammatoryphenotype. Lipid, glucose and insulin metabolism have been show to beimproved in overweight hypertensive subjects through treatment withomega-3 fatty acids.

DHA or EPA, C22 and C20 omega-3 fatty acids, are metabolized to activeanti-inflammatory metabolites, some of which include resolvins andprotectins, and activate various anti-inflammatory pathways.

The ability to simultaneously blunt proinflammatory pathways, forexample those that affect levels of C-reactive protein (CRP), TNFα andIL-6 cytokines, while stimulating anti-inflammatory pathways by shuntingomega-3 fatty acids, such as DHA and EPA, into metabolic pathways thatultimately produce resolvins, protectins and other metabolites thatresolve inflammation would be a great benefit in treating theaforementioned diseases. Inflammation could be particularly vulnerableto a two-pronged attack, inhibiting pro-inflammatory pathways andupregulating anti-inflammatory pathways.

4. SUMMARY OF THE INVENTION

The invention is based in part on the discovery of Fatty Acid AcetylatedSalicylate Derivatives and their demonstrated effects in thesimultaneous upregulation of anti-inflammatory pathways and downregulation of proinflammatory pathways. The invention is also based inpart on the discovery of Fatty Acid Acetylated Diflunisal Derivativesand their upregulation of anti-inflammatory pathways and down regulationof proinflammatory pathways. Additionally, the invention is based inpart on the discovery of Fatty Acid Acetylated Triflusal Derivatives andtheir upregulation of anti-inflammatory pathways and down regulation ofproinflammatory pathways. These novel compounds are useful in thetreatment or prevention of diseases associated with inflammation.

Accordingly, in one aspect, compounds of the Formula I are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

- - - - - represents an optional bond that when present requires that Qis null;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H or

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

Q is null, C(O)CH₃, Z,

e is H or any one of the side chains of the naturally occurring aminoacids;

W₃ is null, —O—, or —N(R)—;

R is H or C₁-C₃ alkyl; and

T is H, C(O)CH₃, or Z.

In another aspect, compounds of the Formula Ia are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

r is 2 or 3; and

s is 5 or 6.

In another aspect compounds of the Formula Ib are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R₁, R₂, R₃, R₄, R₁′, R₂′, R₃′, and R₄′ are each independently selectedfrom the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H,—C(O)C₁-C₃ alkyl, —C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl),—C(O)N(C₁-C₃ alkyl)₂, —C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl,and —S(O)₂C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each of n, o, p, and q is independently 0 or 1;

each Z is H or

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is 0 or 1; and

T is H, C(O)CH₃, or Z.

In another aspect compounds of the Formula Ic are described:

and pharmaceutically acceptable salts, hydrates, solvates, enantiomers,and stereoisomers thereof,wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

n, o, p, and q are each independently 0 or 1;

Z is H, or

each r is independently 2 or 3;

each s is independently 5 or 6; and

t is 0 or 1.

In another aspect, compounds of the Formula Id are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

n, o, p, and q are each independently 0 or 1;

Z is H, or

each r is independently 2 or 3;

each s is independently 5 or 6; and

each t is independently 0 or 1.

In another aspect, compounds of the Formula Ie are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

each Z is independently H, —C(O)CH₃ or

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently s is 5 or 6; and

each t is independently 0 or 1.

In another aspect, compounds of the Formula If are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

W₁ is O, or NH;

W₂ is null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

Z is H, or

each o, p, and q is independently 0 or 1;

each r is independently 2 or 3;

each s is independently 5 or 6; and

each t is independently 0 or 1.

In another aspect, compounds of the Formula Ig are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

W₃ is null, O, or NR;

R is H or C₁-C₃ alkyl;

e is H or any one of the side chains of the naturally occurring aminoacids;

r is 2 or 3; and

s is 5 or 6.

In another aspect, compounds of the Formula II are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

- - - - - represents an optional bond that when present requires that Qis then null;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H or

with the proviso that there is at least one

in the compound;

each r is independently 7;

each s is independently 3;

each t is independently 0 or 1;

Q is null, H, C(O)CH₃, Z,

e is H or any one of the side chains of the naturally occurring aminoacids;

W₃ is null, —O—, or —N(R)—;

R is H or C₁-C₃ alkyl; and

T is H, C(O)CH₃, or Z.

In another aspect, compounds of the Formula III are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

each W₁ and W₂ are independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

- - - - - represents an optional bond that when present requires that Qis null;

each a and c are independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

each b is H, CH₃, C(O)OH, or O—Z;

each d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H or

with the proviso that there is at least one

in the compound;

each r is independently 2, 3, or 7;

each s is independently 3, 5, or 6;

each t is independently 0 or 1;

u is 0 or 1;

with the proviso that when r is 7, s is 3;

Q is null, C(O)CH₃, Z,

e is H or any one of the side chains of the naturally occurring aminoacids;

W₃ is null, —O—, or —N(R)—;

R is H or C₁-C₃ alkyl; and

T is H, C(O)CH₃, or Z.

In yet another aspect, compounds of the Formula IIIa are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

each W₁ and W₂ are independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

- - - - - represents an optional bond that when present requires that Qis null;

each a and c are independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

each b is H, CH₃, C(O)OH, or O—Z;

each d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H or

with the proviso that there is at least one

in the compound;

each r is independently 2, 3, or 7;

each s is independently 3, 5, or 6;

each t is independently 0 or 1;

with the proviso that when r is 7, s is 3;

each Q is null, H, C(O)CH₃, Z,

each e is H or any one of the side chains of the naturally occurringamino acids;

W₃ is null, —O—, or —N(R)—;

R is H or C₁-C₃ alkyl; and

T is H, C(O)CH₃, or Z.

In another aspect, compounds of Formula IV are described herein:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

W₁ and W₂ are each independently null, O, or NH;

- - - - - represents an optional bond that when present requires that Qis null;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H or

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

Q is null, C(O)CH₃, Z, or

e is H, —C(O)OH, or any one of the side chains of the naturallyoccurring amino acids;

W₃ is null, —O—, —N(R)—; and

R is H or C₁-C₃ alkyl.

In another aspect, compounds of the Formula IVa are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

r is 2 or 3; and

s is 5 or 6.

In another aspect, compounds of the Formula IVb are described:

and pharmaceutically acceptable salts, hydrates, solvates, enantiomers,and stereoisomers thereof,

wherein

W₁ and W₂ are each independently null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

Z is H or

each r is independently 2 or 3;

each s is independently 5 or 6; and

t is 0 or 1.

In another aspect, compounds of the Formula IVc are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

W₁ and W₂ are each independently null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each of n, o, p, and q is independently 0 or 1;

each Z is independently null, H, or

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6; and

each t is independently 0 or 1.

In another aspect, compounds of the Formula IVd are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

each Z is independently null, H, or

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently s is 5 or 6; and

each t is independently 0 or 1.

In another aspect, compounds of the Formula IVe are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

W₁ is O, or NH;

W₂ is null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each o, p, and q is independently 0 or 1;

Z is H or

each r is independently 2 or 3;

each s is independently 5 or 6; and

each t is independently 0 or 1.

In another aspect, compounds of the Formula IVf are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

e is H, —C(O)OH or any one of the side chains of the naturally occurringamino acids;

W₃ is null, —O—, —N(R)—; and

R is H or C₁-C₃ alkyl,

r is 2 or 3; and

s is 5 or 6.

In another aspect, compounds of the Formula IVg are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R is H or C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

Z is H or

each r is independently 2 or 3;

each s is independently 5 or 6; and

each t is independently 0 or 1.

In still another aspect, compounds of the Formula V are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

W₁ and W₂ are each independently null, O, or NH;

- - - - - represents an optional bond that when present requires that Qis then null;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is independently null, H, or

with the proviso that there is at least one

in the compound;

each r is independently 7;

each s is independently 3;

each t is independently 0 or 1;

Q is null, C(O)CH₃, Z, or

and

W₃ is null, —O—, —N(R)—;

R is H or C₁-C₃ alkyl and

e is H, —C(O)OH or any one of the side chains of the naturally occurringamino acids.

In yet another aspect, compounds of the Formula VI are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

W₁ and W₂ are each independently null, O, or NH;

- - - - - represents an optional bond that when present requires that Qis null;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H or

with the proviso that there is at least one

in the compound;

each r is independently 0, 1, 2 or 3;

each s is independently an integer from 1 to 10;

each t is independently 0 or 1;

Q is null, C(O)CH₃, Z, or

e is H, —C(O)OH, or any one of the side chains of the naturallyoccurring amino acids;

W₃ is null, —O—, —N(R)—; and

R is H or C₁-C₃ alkyl.

In another aspect, compounds of the Formula VIa are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

r is 2 or 3; and

s is independently 5 or 6.

In another aspect, compounds of the Formula VIb are described:

and pharmaceutically acceptable salts, hydrates, solvates, enantiomers,and stereoisomers thereof,wherein

W₁ and W₂ are each independently null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

Z is H or

each r is independently 2 or 3;

each s is independently 5 or 6; and

each t is independently 0 or 1.

In another aspect, compounds of the Formula VIc are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

W₁ and W₂ are each independently null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each of n, o, p, and q is independently 0 or 1;

each Z is independently null, H, or

with the proviso that at least one Z is

each r is independently 2 or 3;

each s is independently 5 or 6; and

each t is independently 0 or 1.

In another aspect, compounds of the Formula VId are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

each Z is independently H, —C(O)CH₃ or

with the proviso that at least one Z is

each r is independently 2 or 3;

each s is independently 5 or 6; and

each t is independently 0 or 1.

In another aspect, compounds of the Formula VIe are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

W₁ is O, or NH;

W₂ is null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each o, p, and q is independently 0 or 1;

Z is H or

each r is independently 2 or 3;

each s is independently 5 or 6; and

t is independently 0 or 1.

In another aspect, compounds of the Formula VIf are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

e is H, —C(O)OH or any one of the side chains of the naturally occurringamino acids;

W₃ is null, —O—, —N(R)—; and

R is H or C₁-C₃ alkyl,

r is 2 or 3;

s is 5 or 6; and

t is 0 or 1.

In another aspect, compounds of the Formula VIg are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R is H or C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

Z is H or

each r is independently 2 or 3;

each s is independently 5 or 6; and

each t is independently 0 or 1.

In another aspect, compounds of the Formula VII are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

W₁ and W₂ are each independently null, O, or NH;

- - - - - represents an optional bond that when present requires that Qis then null;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H or

with the proviso that there is at least one

in the compound;

each r is independently 7;

each s is independently 3;

each t is independently 0 or 1;

Q is null, C(O)CH₃, Z, or

and

W₃ is null, —O—, —N(R)—;

R is H or C₁-C₃ alkyl; and

e is H, —C(O)OH or any one of the side chains of the naturally occurringamino acids.

In a further aspect, compounds of the Formula I′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

- - - - - represents an optional bond that when present requires that Qis null;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl;

Q is null, C(O)CH₃, Z,

e is H or any one of the side chains of the naturally occurring aminoacids;

W₃ is null, —O—, or —N(R)—;

R is H or C₁-C₃ alkyl; and

T is H, C(O)CH₃, or Z.

In another aspect, compounds of the Formula Ia′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

s is 5 or 6;

v is 1 or 2; and

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In another aspect compounds of the Formula Ib′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

R₁, R₂, R₃, R₄, R₁′, R₂′, R₃′, and R₄′ are each independently selectedfrom the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H,—C(O)C₁-C₃ alkyl, —C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl),—C(O)N(C₁-C₃ alkyl)₂, —C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl,and —S(O)₂C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each of n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl; and

T is H, C(O)CH₃, or Z.

In another aspect compounds of the Formula Ic′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, enantiomers,and stereoisomers thereof,

wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

n, o, p, and q are each independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2; and

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In another aspect, compounds of the Formula Id′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

n, o, p, and q are each independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2; and

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In another aspect, compounds of the Formula Ie′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

each Z is independently H, —C(O)CH₃,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently s is 5 or 6; and

each t is independently 0 or 1

each v is 1 or 2; and

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In another aspect, compounds of the Formula If′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

W₁ is O, or NH;

W₂ is null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In another aspect, compounds of the Formula Ig′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

W₃ is null, O, or NH;

e is H or any one of the side chains of the naturally occurring aminoacids;

v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl; and

s is 5 or 6.

In another aspect, compounds of the Formula II′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

- - - - - represents an optional bond that when present requires that Qis then null;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is 7;

each s is 3;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl;

Q is null, C(O)CH₃, Z,

e is H or any one of the side chains of the naturally occurring aminoacids;

W₃ is null, —O—, or —N(R)—;

R is H or C₁-C₃ alkyl; and

T is H, C(O)CH₃, or Z.

In another aspect, compounds of the Formula III′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

each W₁ and W₂ are independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

- - - - - represents an optional bond that when present requires that Qis null;

each a and c are independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

each b is H, CH₃, C(O)OH, or O—Z;

each d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2, 3, or 7;

each s is independently 3, 5, or 6;

each t is independently 0 or 1;

each v is 1 or 2;

each R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl;

u is 0 or 1;

with the proviso that when r is 7, s is 3;

Q is null, C(O)CH₃, Z,

e is H or any one of the side chains of the naturally occurring aminoacids;

W₃ is null, —O—, or —N(R)—;

R is H or C₁-C₃ alkyl; and

T is H, C(O)CH₃, or Z.

In yet another aspect, compounds of the Formula IIIa′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

each W₁ and W₂ are independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

- - - - - represents an optional bond that when present requires that Qis null;

each a and c are independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

each b is H, CH₃, C(O)OH, or O—Z;

each d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2, 3, or 7;

each s is independently 3, 5, or 6;

each t is independently 0 or 1;

each v is 1 or 2;

each R₅ and R₆ are independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl;

with the proviso that when r is 7, s is 3;

each Q is null, C(O)CH₃, Z,

each e is H or any one of the side chains of the naturally occurringamino acids;

W₃ is null, —O—, or —N(R)—;

R is H or C₁-C₃ alkyl; and

T is H, C(O)CH₃, or Z.

In another aspect, compounds of Formula IV′ are described herein:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

W₁ and W₂ are each independently null, O, or NH;

- - - - - represents an optional bond that when present requires that Qis null;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl;

Q is null, C(O)CH₃, Z, or

e is H, —C(O)OH, or any one of the side chains of the naturallyoccurring amino acids;

W₃ is null, —O—, —N(R)—; and

R is H or C₁-C₃ alkyl.

In another aspect, compounds of the Formula IVa′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl; and

s is 5 or 6.

In another aspect, compounds of the Formula IVb′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, enantiomers,and stereoisomers thereof,

wherein

W₁ and W₂ are each independently null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In another aspect, compounds of the Formula IVc′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

W₁ and W₂ are each independently null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each of n, o, p, and q is independently 0 or 1;

each Z is null, H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In another aspect, compounds of the Formula IVd′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

each Z is null, H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In another aspect, compounds of the Formula IVe′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

W₁ is O, or NH;

W₂ is null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In another aspect, compounds of the Formula IVf′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl;

e is H, —C(O)OH or any one of the side chains of the naturally occurringamino acids;

W₃ is null, —O—, —N(R)—; and

R is H or C₁-C₃ alkyl,

v is 1 or 2;

s is 5 or 6.

In another aspect, compounds of the Formula IVg′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R is H or C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In still another aspect, compounds of the Formula V′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

W₁ and W₂ are each independently null, O, or NH;

- - - - - represents an optional bond that when present requires that Qis then null;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is independently null, H,

with the proviso that there is at least one

in the compound;

each r is independently 7;

each s is independently 3;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl;

Q is null, C(O)CH₃, Z, or

W₃ is null, —O—, —N(R)—;

R is H or C₁-C₃ alkyl; and

e is H, —C(O)OH or any one of the side chains of the naturally occurringamino acids.

In yet another aspect, compounds of the Formula VI′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

W₁ and W₂ are each independently null, O, or NH;

- - - - - represents an optional bond that when present requires that Qis null;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 0, 1, 2, or 3;

each s is independently an integer from 1 to 10;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl;

Q is null, C(O)CH₃, Z, or

e is H, —C(O)OH, or any one of the side chains of the naturallyoccurring amino acids;

W₃ is null, —O—, —N(R)—; and

R is H or C₁-C₃ alkyl.

In another aspect, compounds of the Formula VIa′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

v is 1 or 2; R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄alkyl, halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄alkyl, —C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂,—SH, —S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl; and

s is independently 5 or 6.

In another aspect, compounds of the Formula VIb′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, enantiomers,and stereoisomers thereof,

wherein

W₁ and W₂ are each independently null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In another aspect, compounds of the Formula VIc′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

W₁ and W₂ are each independently null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each of n, o, p, and q is independently 0 or 1;

each Z is independently null, H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In another aspect, compounds of the Formula VId′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

each Z is independently H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In another aspect, compounds of the Formula VIe′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

W₁ is O, or NH;

W₂ is null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In another aspect, compounds of the Formula VIf′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

e is H, —C(O)OH or any one of the side chains of the naturally occurringamino acids;

W₃ is null, —O—, —N(R)—; and

R is H or C₁-C₃ alkyl,

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl;

s is 5 or 6.

In another aspect, compounds of the Formula VIg′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R is H or C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In another aspect, compounds of the Formula VII′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

W₁ and W₂ are each independently null, O, or NH;

- - - - - represents an optional bond that when present requires that Qis then null;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 7;

each s is independently 3;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl;

Q is null, C(O)CH₃, Z, or

and

W₃ is null, —O—, —N(R)—;

R is H or C₁-C₃ alkyl; and

e is H, —C(O)OH or any one of the side chains of the naturally occurringamino acids.

In any of the above Formulae, any one or more of H may be substitutedwith a deuterium. It is also understood in any of the above Formulaethat a methyl subtituent can be substituted with a C₁-C₆ alkyl.

Also described are pharmaceutical formulations comprising at least oneCompound of the Invention.

Also described herein are methods of simultaneously up regulatingantiinflammation pathways and down regulating proinflammation pathwaysin a cell by administering to the cell a Compound of the Invention.

Also described herein are methods of simultaneously up regulatingantiinflammation pathways and down regulating proinflammation pathwaysin a patient in need thereof, by administering to the patient aneffective amount of a Compound of the Invention.

Also described herein are methods of treating a disease susceptible totreatment with a Compound of the Invention in a patient in need thereofby administering to the patient an effective amount of a Compound of theInvention.

Also described herein are methods of treating diseases associated withinflammation by administering to a patient in need thereof an effectiveamount of a Compound of the Invention.

The invention also includes pharmaceutical compositions that comprise aneffective amount of a Compound of the Invention and a pharmaceuticallyacceptable carrier. The compositions are useful for treating orpreventing an inflammatory disease. The invention includes a Compound ofthe Invention when provided as a pharmaceutically acceptable prodrug, ahydrate, a salt, such as a pharmaceutically acceptable salt, enantiomer,stereoisomer, or mixtures thereof.

The details of the invention are set forth in the accompanyingdescription below. Although any methods and materials similar orequivalent to those described herein can be used in the practice ortesting of the present invention, illustrative methods and materials arenow described. Other features, objects, and advantages of the inventionwill be apparent from the description and from the claims. In thespecification and the appended claims, the singular forms also includethe plural unless the context clearly dictates otherwise. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this invention belongs. All patents and publications cited in thisspecification are incorporated herein by reference in their entireties.

5. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graphic representation of the data showing the effects of aCompound of the Invention on IL-10 levels in 3T3-L1 adipocytes.

FIG. 2 is a graphic representation of the data showing the effects of aCompound of the Invention on TNFα release.

FIG. 3 is graphic representation of the data showing the in vivo effectsof Compounds of the Invention in an LPS-challenge TNFα mouse model.

6. DETAILED DESCRIPTION OF THE INVENTION

Inflammation is the underlying cause of and pathological contributor tomany chronic diseases including type 2 diabetes, rheumatoid arthritis,psoriasis, inflammatory bowel disease, Parkinson's disease, Alzheimer'sdisease, multiple sclerosis, epilepsy, and cancer, etc. Inflammation isthe body's natural protective response to insult, injury and infection.The normal inflammatory process is highly regulated. The process isinitiated by a stimulus which leads to the induction of pro-inflammatorypathways. The response persists while the stimulus is present and isturned off during the resolving phase of inflammation. During each ofthese phases of the inflammatory response different enzymes, receptors,and effectors, are activated and inactivated. If the stimulus persists,chronic inflammation ensues and results in an imbalance in the pro- andanti-inflammatory pathways. Current therapies that target inflammationhave been directed in general at single molecular targets or effectorsin single pathways. For example, TNFα antibodies, TNFα solublereceptors, COX-2 inhibitors, CCR2 antagonists, p38 inhibitors, etc.target just the pro-inflammatory arm of inflammation. In general theseapproaches are not disease modifying and are associated with sideeffects that result from an imbalanced inflammatory response. Thesimultaneous targeting of both the pro- and anti-inflammatory pathwaysin the normal inflammatory response provides superior activity intargeting inflammation, disease modifying activity, and a reduced sideeffect profile. The Compounds of the Invention possess the ability toinhibit pro-inflammatory pathways, while simultaneously activatinganti-inflammatory pathways. The simultaneous targeting of these pathwaysleads to synergistic efficacy and thus the two activities must bedelivered to the target cell and/or tissue together.

The Compounds of the Invention have been designed to bring togethersalicylate analogs and omega 3 fatty acids into a single molecularconjugate. Salicylate analogs inhibit the pro-inflammatory pathwaythrough inhibition of NFκB. The omega 3 fatty acids including DHA, EPA,and ALA activate the anti-inflammatory pathway. The Compounds of theInvention thus possess two activities—the ability to bluntpro-inflammatory activity and the ability to activate anti-inflammatoryactivity. Compounds of the Invention exhibit potent NFκB and TNFαinhibitory activity in a mouse macrophage cell line, RAW264.7, while theindividual components, a salicylate analog and a EFA, alone or incombination together, do not. The activity of the Compounds of theInvention is substantially greater than the sum of the componentssuggesting that the activity induced by the Compounds of the Inventionis synergistic.

DEFINITIONS

The following definitions are used in connection with the Fatty AcidAcetylated Salicylate Derivatives, the Fatty Acid Acetylated DiflunisalDerivatives, and Fatty Acid Acetylated Triflusal Derivatives:

The term “Compound of the Invention” refers to a Fatty Acid AcetylatedSalicylate Derivative described herein, wherein Salicylate Derivativeincludes, without limitation, salicylic acid and substituted salicylatessuch as aminosalicylic acid, a Fatty Acid Acetylated DiflunisalDerivative described herein, or a Fatty Acid Acetylated TriflusalDerivative described herein. The term “Compounds of the Invention”refers to more than one Compound of the Invention and may be Fatty AcidAcetylated Salicylate Derivatives, Fatty Acid Acetylated DiflunisalDerivatives, Fatty Acid Acetylated Triflusal Derivatives, or somecombination thereof. The Compounds of the Invention include any and allpossible isomers, stereoisomers, enantiomers, diastereomers, tautomers,pharmaceutically acceptable salts, hydrates, solvates, and prodrugsthereof.

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

Unless otherwise specifically defined, the term “aryl” refers to cyclic,aromatic hydrocarbon groups that have 1 to 2 aromatic rings, includingmonocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl.Where containing two aromatic rings (bicyclic, etc.), the aromatic ringsof the aryl group may be joined at a single point (e.g., biphenyl), orfused (e.g., naphthyl). The aryl group may be optionally substituted byone or more substituents, e.g., 1 to 5 substituents, at any point ofattachment. The substituents can themselves be optionally substituted.

“C₁-C₃ alkyl” refers to a straight or branched chain saturatedhydrocarbon containing 1-3 carbon atoms. Examples of a C₁-C₃ alkyl groupinclude, but are not limited to, methyl, ethyl, propyl and isopropyl.

“C₁-C₄ alkyl” refers to a straight or branched chain saturatedhydrocarbon containing 1-4 carbon atoms. Examples of a C₁-C₄ alkyl groupinclude, but are not limited to, methyl, ethyl, propyl, butyl,isopropyl, isobutyl, sec-butyl and tert-butyl.

“C₁-C₅ alkyl” refers to a straight or branched chain saturatedhydrocarbon containing 1-5 carbon atoms. Examples of a C₁-C₅ alkyl groupinclude, but are not limited to, methyl, ethyl, propyl, butyl, pentyl,isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl.

“C₁-C₆ alkyl” refers to a straight or branched chain saturatedhydrocarbon containing 1-6 carbon atoms. Examples of a C₁-C₆ alkyl groupinclude, but are not limited to, methyl, ethyl, propyl, butyl, pentyl,hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, andneopentyl.

The term “any one of the side chains of the naturally occurring aminoacids” as used herein means a side chain of any one of the followingamino acids: Isoleucine, Alanine, Leucine, Asparagine, Lysine,Aspartate, Methionine, Cysteine, Phenylalanine, Glutamate, Threonine,Glutamine, Tryptophan, Glycine, Valine, Proline, Arginine, Serine,Histidine, and Tyrosine.

The term “fatty acid” as used herein means an omega-3 fatty acid andfatty acids that are metabolized in vivo to omega-3 fatty acids.Non-limiting examples of fatty acids areall-cis-7,10,13-hexadecatrienoic acid, α-linolenic acid (ALA orall-cis-9,12,15-octadecatrienoic acid), stearidonic acid (STD orall-cis-6,9,12,15-octadecatetraenoic acid), eicosatrienoic acid (ETE orall-cis-11,14,17-eicosatrienoic acid), eicosatetraenoic acid (ETA orall-cis-8,11,14,17-eicosatetraenoic acid), eicosapentaenoic acid (EPA orall-cis-5,8,11,14,17-eicosapentaenoic acid), docosapentaenoic acid (DPA,clupanodonic acid or all-cis-7,10,13,16,19-docosapentaenoic acid),docosahexaenoic acid (DHA or all-cis-4,7,10,13,16,19-docosahexaenoicacid), tetracosapentaenoic acid (all-cis-9,12,15,18,21-docosahexaenoicacid), or tetracosahexaenoic acid (nisinic acid orall-cis-6,9,12,15,18,21-tetracosenoic acid).

A “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog,cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

The invention also includes pharmaceutical compositions comprising aneffective amount of a Compound of the Invention and a pharmaceuticallyacceptable carrier. The invention includes a Compound of the Inventionwhen provided as a pharmaceutically acceptable prodrug, hydrate, salt,such as a pharmaceutically acceptable salt, enantiomers, stereoisomers,or mixtures thereof.

Representative “pharmaceutically acceptable salts” include, e.g.,water-soluble and water-insoluble salts, such as the acetate, amsonate(4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate,bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium,calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate,dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate,gluceptate, gluconate, glutamate, glycollylarsanilate,hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts.

An “effective amount” when used in connection with a Compound of theInvention is an amount effective for treating or preventing aninflammatory disease.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating can be curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwised indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a compound orpharmaceutically acceptable salt of the compound or a composition to asubject, or administering a prodrug derivative or analog of the compoundor pharmaceutically acceptable salt of the compound or composition tothe subject, which can form an equivalent amount of active compoundwithin the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to aCompound of the Invention.

The following abbreviations are used herein and have the indicateddefinitions: DCC is dicyclohexylcarbodiimide, CDI is1,1′-carbonyldiimidazole, EDC is1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride, HEPES is4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, SA is salicylicacid, 5-ASA is 5-aminosalicylic acid, SDS is dodecyl sulfate (sodiumsalt), TNF is tumor necrosis factor, TRIS isTris(hydroxymethyl)aminomethane, Ts is tosyl (p-toluenesulfonyl), RT isroom temperature, and h is hour.

Compounds

The present invention provides Fatty Acid Acetylated SalicylateDerivatives according to Formula I, Formula Ia, Formula Ib, Formula Ic,Formula Id, Formula Ie, Formula If, Formula Ig, Formula II, and FormulaIII as set forth below. The present invention also provides, a FattyAcid Acetylated Diflunisal Derivatives according to Formula IV, FormulaIVa, Formula IVb, Formula IVc, Formula IVd, Formula IVe, Formula IVf,Formula IVg, and Formula V, as set forth below. The present inventionadditionally provides Fatty Acid Acetylated Triflusal Derivativesaccording to Formula VI, Formula VIa, Formula VIb, Formula VIc, FormulaVId, Formula VIe, Formula VIf, Formula VIg, and Formula VII, as setforth below.

Described herein are compounds of the Formula I:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R₁, R₂, R₃, R₄, W₁, W₂, a, b, c, d, e, the symbol - - - - -, Z, n, o, p,q, r, s, t, Q, and T are as defined above for compounds of Formula I.

In some embodiments, R₂ is Cl or F.

In other embodiments, R₃ is Cl or F.

In some embodiments, W₁ is O.

In some embodiments, W₂ is O.

In some embodiments, W₁ is N. In other embodiments W₁ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₁ is an oxidized N.

In some embodiments, W₂ is N. In other embodiments W₂ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₂ is an oxidized N.

In some embodiments, - - - - - represents a bond.

In some embodiments, a and c are each independently H, CH₃, —OCH₃,OCH₂CH₃, or C(O)OH;

In some embodiments, b is O—Z, Z is

and t is 1.

In some embodiments, d is C(O)OH.

In some embodiments n, o, p, and q are each 1.

In some embodiments, n is 0.

In some embodiments, Z is

and r is 2.

In some embodiments, Z is

and r is 3.

In some embodiments, Z is

and s is 5.

In some embodiments, Z is

and s is 6.

In some embodiments, t is 1.

In some embodiments, Q is C(O)CH₃.

In some embodiments, Q is Z.

In some embodiments, Q is

In some embodiments, Q is

In some embodiments, T is H.

In some embodiments, T is C(O)CH₃.

In some embodiments, T is Z.

In some embodiments, e is any one of the side chains of the naturallyoccurring amino acids.

In some embodiments, e is H.

In other illustrative embodiments, compounds of the Formula I are as setforth below:

Described herein are compounds of the Formula Ia:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

R₁, R₂, R₃, R₄, r, and s are as defined above for compounds of FormulaIa.

In some embodiments, R₂ is Cl or F.

In other embodiments, R₃ is Cl or F.

In some embodiments, r is 2.

In some embodiments, r is 3.

In some embodiments, s is 5.

In some embodiments, s is 6.

In some embodiments, t is 1.

In other illustrative embodiments, compounds of Formula Ia are as setforth below:

Described herein are compounds of the Formula Ib:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;whereinR₁, R₂, R₃, R₄, R₁′, R₂′, R₃′, R₄′ and W₁, W₂, a, c, b, d, n, o, p, q,Z, r, s, t, and T are as defined above for the compounds of Formula Ib.

In some embodiments, R₂ is Cl or F.

In other embodiments, R₃ is Cl or F.

In some embodiments, W₁ is O.

In some embodiments, W₂ is O.

In some embodiments, a and c are each independently H, CH₃, —OCH₃,—OCH₂CH₃, or C(O)OH;

In some embodiments, b is O—Z, Z is

and t is 1.

In some embodiments, d is C(O)OH.

In some embodiments n, o, p, and q are each 1.

In some embodiments, n is 0.

In some embodiments, Z is

and r is 2.

In some embodiments, Z is

and r is 3.

In some embodiments, Z is

and s is 5.

In some embodiments, Z is

and s is 6.

In some embodiments, t is 1.

In some embodiments, T is H.

In some embodiments, T is C(O)CH₃.

In some embodiments, T is Z.

In other illustrative embodiments, compounds of Formula Ib are as setforth below:

In another aspect, compounds of the Formula Ic are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

R₁, R₂, R₃, R₄, W₁, W₂, a, c, b, d, n, o, p, q, Z, r, s, and t are asdefined above for the compounds of the Formula Ic.

In some embodiments, R₂ is Cl or F.

In other embodiments, R₃ is Cl or F.

In some embodiments, W₁ is O.

In some embodiments, W₂ is O.

In some embodiments, a and c are each independently H, CH₃, —OCH₃,—OCH₂CH₃, or C(O)OH.

In some embodiments, b is O—Z, Z is

and t is 1.

In some embodiments, d is C(O)OH.

In some embodiments n, o, p, and q are each 1.

In some embodiments, n is 0.

In some embodiments, Z is

and r is 2.

In some embodiments, Z is

and r is 3.

In some embodiments, Z is

and s is 5.

In some embodiments, Z is

and s is 6.

In some embodiments, t is 1.

In some embodiments, T is H.

In some embodiments, T is C(O)CH₃.

In some embodiments, T is Z.

In other illustrative embodiments, compounds of Formula Ic are as setforth below:

In another aspect, compounds of the Formula Id are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

R₁, R₂, R₃, R₄ W₁, W₂, a, b, c, d, n, o, p, q, Z, r, s, and t are asdefined above for the compounds of the Formula Id.

In some embodiments, R₂ is Cl or F.

In other embodiments, R₃ is Cl or F.

In some embodiments, W₁ is O.

In some embodiments, W₂ is O.

In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

In some embodiments, b is O—Z, Z is

and t is 1.

In some embodiments, d is C(O)OH.

In some embodiments n, o, p, and q are each 1.

In some embodiments, n is 0.

In some embodiments, Z is

and r is 2.

In some embodiments, Z is

and r is 3.

In some embodiments, Z is

and s is 5.

In some embodiments, Z is

and s is 6.

In some embodiments, t is 1.

In some embodiments, T is H.

In some embodiments, T is C(O)CH₃.

In some embodiments, T is Z.

In other illustrative embodiments, compounds of Formula Id are as setforth below:

In another aspect, compounds of the Formula Ie are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R₁, R₂, R₃, R₄, Z, r, s, and t are as defined above for the compounds ofFormula Ie.

In some embodiments, R₂ is Cl or F.

In other embodiments, R₃ is Cl or F.

In some embodiments, Z is

and r is 2.

In some embodiments, Z is

and r is 3.

In some embodiments, Z is

and s is 5.

In some embodiments, Z is

and s is 6.

In some embodiments, t is 1.

In other illustrative embodiments, compounds of Formula Ie are as setforth below:

In another aspect, compounds of the Formula If are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

R₁, R₂, R₃, R₄ W₁, W₂, a, b, c, d, Z, o, p, q, r, s, and t are asdefined above for the compounds of the Formula If.

In some embodiments, R₂ is Cl or F.

In other embodiments, R₃ is Cl or F.

In some embodiments, W₁ is O.

In some embodiments, W₂ is O.

In some embodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

In some embodiments, b is O—Z, Z is

and t is 1.

In some embodiments, d is C(O)OH.

In some embodiments n, o, p, and q are each 1.

In some embodiments, n is 0.

In some embodiments, Z is

and r is 2.

In some embodiments, Z is

and r is 3.

In some embodiments, Z is

and s is 5.

In some embodiments, Z is

and s is 6.

In some embodiments, t is 1.

In other illustrative embodiments, compounds of Formula If are as setforth below:

In another aspect, compounds of the Formula Ig are described.

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;whereinR₁, R₂, R₃, R₄, W₃, R, e, r, and s are as described above for thecompounds of Formula Ig.

In some embodiments, W₃ is O.

In some embodiments, e is sec-butyl.

In some embodiments, e is any one of the side chains of the naturallyoccurring amino acids.

In some embodiments, r is 2.

In some embodiments, r is 3.

In some embodiments, s is 5.

In some embodiments, s is 6.

In some embodiments, t is 1.

In other illustrative embodiments, compounds of Formula Ig are as setforth below:

In another aspect, compounds of the Formula II are described

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R₁, R₂, R₃, R₄, W₁, W₂, a, b, c, d, e, the symbol - - - - -, Z, n, o, p,q, r, s, t, Q, and T are as defined above for compounds of Formula II.

In some embodiments, R₂ is Cl or F. In other embodiments, R₃ is Cl or F.In some embodiments, W₁ is O. In some embodiments, W₂ is O.

In some embodiments, W₁ is N. In other embodiments W₁ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₁ is an oxidized N.

In some embodiments, W₂ is N. In other embodiments W₂ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₂ is an oxidized N.

In some embodiments, - - - - - represents a bond. In some embodiments, aand c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In someembodiments, b is O—Z and Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and R is 7. In other embodiments, Z is

and S is 3. In some embodiments, t is 1. In some embodiments, Q isC(O)CH₃. In some embodiments, Q is Z. In some embodiments, Q is

In some embodiments, Q is

In some embodiments, T is H. In some embodiments, T is C(O)CH₃. In someembodiments, T is Z. In some embodiments, e is any one of the sidechains of the naturally occurring amino acids. In some embodiments, e isH.

In another aspect, compounds of Formula III are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

W₁, W₂, - - - - -, a, b, c, d, n, o, p, q, Z, r, s, t, u, Q, T, e, W₃, Rare as defined above for compounds of Formula III.

In some embodiments, R₂ is Cl or F. In other embodiments, R₃ is Cl or F.In some embodiments, W₁ is O. In some embodiments, W₂ is O.

In some embodiments, W₁ is N. In other embodiments W₁ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₁ is an oxidized N.

In some embodiments, W₂ is N. In other embodiments W₂ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₂ is an oxidized N.

In some embodiments, - - - - - represents a bond. In some embodiments, aand c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In someembodiments, b is O—Z and Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, t is 1. In some embodiments, Q isC(O)CH₃. In some embodiments, Q is Z. In some embodiments, Q is

In some embodiments, Q is

In some embodiments, T is H. In some embodiments, T is C(O)CH₃. In someembodiments, T is Z. In some embodiments, e is any one of the sidechains of the naturally occurring amino acids. In some embodiments, e isH.

In yet another aspect, compounds of the Formula IIIa are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

W₁, W₂, - - - - -, a, b, c, d, n, o, p, q, Z, r, s, t, Q, T, e, W₃, Rare as defined above for compounds of Formula IIIa.

In some embodiments, W₁ is O. In some embodiments, W₂ is O.

In some embodiments, W₁ is N. In other embodiments W₁ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₁ is an oxidized N.

In some embodiments, W₂ is N. In other embodiments W₂ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₂ is an oxidized N.

In some embodiments, - - - - - represents a bond. In some embodiments, aand c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In someembodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, t is 1. In some embodiments, Q isC(O)CH₃. In some embodiments, Q is Z. In some embodiments, Q is

In some embodiments, W₃ is O. In other embodiments, W₃ is N(R). Infurther embodiments, W₃ is NH. In some embodiments, e is any one of theside chains of the naturally occurring amino acids. In some embodiments,e is H.

In some embodiments, Q is

In some embodiments, T is H. In some embodiments, T is C(O)CH₃. In someembodiments, T is Z. In some embodiments, e is any one of the sidechains of the naturally occurring amino acids. In some embodiments, e isH.

In other illustrative embodiments, compounds of Formula III and IIIa areas set forth below:

Compounds of the Formula IV are also described herein:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein W₁, W₂, - - - - -, a, b, c, d n, o, p, q, Z, r, s, t, u, Q, e,W₃, and R are as defined as above for Formula IV.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH.

In some embodiments, W₁ is N. In other embodiments W₁ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₁ is an oxidized N.

In some embodiments, W₂ is N. In other embodiments W₂ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₂ is an oxidized N.

In some embodiments, - - - - - represents a bond. In some embodiments, aand c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In someembodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, t is 1. In some embodiments, Q is H. Inother embodiments, Q is C(O)CH₃. In some embodiments, Q is Z. In someembodiments, Q is

In some embodiments, e is any one of the side chains of the naturallyoccurring amino acids. In some embodiments, e is H. In otherembodiments, e is —C(O)OH. In some embodiments, W₃ is —NR—. In someembodiments, W₃ is O.

In another aspect, compounds of the Formula IVa are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein r and are as defined above for Formula IVa.

In some embodiments, r is 2. In some embodiments, r is 3. In someembodiments, s is 5. In some embodiments, s is 6.

Illustrative compounds of Formula IVa include:

In another aspect, compounds of the Formula IVb are described:

and pharmaceutically acceptable salts, hydrates, solvates, enantiomers,and stereoisomers thereof,

wherein W₁, W₂, a, b, c, d n, o, p, q, Z r, s, and t are as definedabove for Formula IVb.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, orC(O)OH; In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0.

In some embodiments, Z is

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In other embodiments, Z is not H. In some embodiments, t is1.

Illustrative compounds of Formula IVb include:

In another aspect, compounds of the Formula IVc are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein W₁, W₂, a, b, c, d, n, o, p, q, Z, r, s, and t are as definedabove for Formula IVc.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —O CH₂CH₃, orC(O)OH; In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, at most one Z is H. In someembodiments, Z is not H. In other embodiments, Z is not —C(O)CH₃. Insome embodiments, t is 1.

Illustrative compounds of Formula IVc are:

In another aspect, compounds of the Formula IVd are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein Z, r, s, and t are as defined above for Formula IVd.

In some embodiments, Z is

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, t is 1.

In another aspect, compounds of the Formula IVe are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein W₁, W₂ a, b, c, d, o, p, q, Z, r, s, t, and u are as definedabove for Formula IVe.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, orC(O)OH. In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, t is 1.

An illustrative compound of Formula IVe is:

In another aspect, compounds of the Formula IVf are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein e, W₃, R, r, and s are as defined above for Formula IVf.

In some embodiments, W₃ is O. In some embodiments, e is sec-butyl. Inother embodiments, e is —C(O)OH. In still other embodiments, e is H. Insome embodiments, W₃ is —NR—. In some embodiments, W₃ is O. In someembodiments, Z is

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, t is 1.

Illustrative compounds of Formula IVf include:

In another aspect, compounds of the Formula IVg are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein R, W₁, W₂, a, b, c, d, n, o, p, q, Z, r, s, and t are as definedabove for Formula IVg.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —O CH₂CH₃, orC(O)OH; In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, at most one Z is H. In someembodiments, Z is not H. In other embodiments, Z is not —C(O)CH₃. Insome embodiments, t is 1.

Illustrative compounds of Formula IVg include:

In another aspect, compounds of the Formula V are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein W₁, W₂, - - - - -, Q, a, b, c, d, e, W₃, n, o, p, q, Z, r, s,and t are as defined above for Formula V.

In some embodiments, W₁ is O. In some embodiments, W₁ is NH. In someembodiments, W₂ is O. In some embodiments, W₂ is NH.

In some embodiments, W₁ is N. In other embodiments W₁ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₁ is an oxidized N.

In some embodiments, W₂ is N. In other embodiments W₂ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₂ is an oxidized N.

In some embodiments, - - - - - represents a bond. In some embodiments, aand c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In someembodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 7. In some embodiments, Z is

and s is 3. In some embodiments, t is 1. In some embodiments, Q isC(O)CH₃, In some embodiments, Q is Z. In some embodiments, Q is

In some embodiments, e is any one of the side chains of the naturallyoccurring amino acids. In some embodiments, e is H. In otherembodiments, e is —C(O)OH. In some embodiments, W₃ is —NR—. In someembodiments, W₃ is O.

Also described herein are compounds of the Formula VI:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein W₁, W₂, - - - - -, a, b, c, d n, o, p, q, Z, r, s, t, u, Q, e,W₃, and R are as defined above for Formula VI.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH.

In some embodiments, W₁ is N. In other embodiments W₁ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₁ is an oxidized N.

In some embodiments, W₂ is N. In other embodiments W₂ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₂ is an oxidized N.

In some embodiments, - - - - - represents a bond. In some embodiments, aand c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In someembodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, t is 1. In some embodiments, Q is H. Inother embodiments, Q is C(O)CH₃. In some embodiments, Q is Z. In someembodiments, Q is

In some embodiments, e is any one of the side chains of the naturallyoccurring amino acids. In some embodiments, e is H. In otherembodiments, e is —C(O)OH. In some embodiments, W₃ is —NH—. In someembodiments, W₃ is O.

In another aspect, compounds of the Formula VIa are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein r and s are as defined above for Formula VIa.

In some embodiments, r is 2. In some embodiments, r is 3. In someembodiments, s is 5. In some embodiments, s is 6.

Illustrative compounds of Formula VIa include:

In another aspect, compounds of the Formula VIb are described:

and pharmaceutically acceptable salts, hydrates, solvates, enantiomers,and stereoisomers thereof,

wherein W₁, W₂, a, b, c, d n, o, p, q, Z r, s, and t are as definedabove for Formula VIb.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, orC(O)OH; In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0.

In some embodiments, Z is

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, t is 1.

Illustrative compounds of Formula VIb include:

In another aspect, compounds of the Formula VIc are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein W₁, W₂, a, b, c, d, n, o, p, q, Z, r, s, and t are as definedabove for Formula VIc.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —O CH₂CH₃, orC(O)OH; In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1.

In some embodiments, n is 0. In some embodiments, Z is

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, at most one Z is H. In someembodiments, Z is not H. In other embodiments, Z is not —C(O)CH₃. Insome embodiments, t is 1.

Illustrative compounds of Formula VIc are:

In another aspect, compounds of the Formula VId are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein Z, r, s, and t are as defined above for Formula VId.

In some embodiments, Z is

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, t is 1.

In another aspect, compounds of the Formula VIe are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein W₁, W₂, a, b, c, d, o, p, q, Z, r, s, and t, are as definedabove for Formula VIe.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, orC(O)OH. In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1.

In some embodiments, n is 0. In some embodiments, Z is

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, t is 1.

An illustrative compound of Formula VIe is:

In another aspect, compounds of the Formula VIf are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein e, W₃, R, r, s, and t are as defined above for Formula VIf.

In some embodiments, W₃ is O. In some embodiments, e is sec-butyl. Inother embodiments, e is —C(O)OH. In still other embodiments, e is H. Insome embodiments, W₃ is —NR—. In some embodiments, W₃ is O. In someembodiments, r is 2. In some embodiments, r is 3. In some embodiments, sis 5. In some embodiments, s is 6. In some embodiments, t is 1.

Illustrative compounds of Formula VIf include:

In another aspect, compounds of the Formula VIg are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein R, W¹, W², a, b, c, d, n, o, p, q, Z, r, s, and t are as definedabove for Formula VIg.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —O CH₂CH₃, orC(O)OH; In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, at most one Z is H. In someembodiments, Z is not H. In other embodiments, Z is not —C(O)CH₃. Insome embodiments, t is 1.

Illustrative compounds of Formula VIg include:

In another aspect, compounds of the Formula VII are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein W₁, W₂, - - - - -, Q, a, b, c, d, e, W₃, n, o, p, q, Z, r, s,and t are as defined above for Formula VII.

In some embodiments, W₁ is O. In some embodiments, W₁ is NH. In someembodiments, W₂ is O. In some embodiments, W₂ is NH.

In some embodiments, W₁ is N. In other embodiments W₁ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₁ is an oxidized N.

In some embodiments, W₂ is N. In other embodiments W₂ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₂ is an oxidized N.

In some embodiments, - - - - - represents a bond. In some embodiments, aand c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In someembodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 7. In some embodiments, Z is

and s is 3. In some embodiments, t is 1. In some embodiments, Q isC(O)CH₃, In some embodiments, Q is Z. In some embodiments, Q is

In some embodiments, e is any one of the side chains of the naturallyoccurring amino acids. In some embodiments, e is H. In otherembodiments, e is —C(O)OH. In some embodiments, W₃ is —NR—. In someembodiments, W₃ is O.

In a further aspect, compounds of the Formula I′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

- - - - - represents an optional bond that when present requires that Qis null;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl;

Q is null, C(O)CH₃, Z,

e is H or any one of the side chains of the naturally occurring aminoacids;

W₃ is null, —O—, or —N(R)—;

R is H or C₁-C₃ alkyl; and

T is H, C(O)CH₃, or Z.

In some embodiments, R₂ is Cl or F. In other embodiments, R₃ is Cl or F.In some embodiments, W₁ is O. In some embodiments, W₂ is O.

In some embodiments, W₁ is N. In other embodiments W₁ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₁ is an oxidized N.

In some embodiments, W₂ is N. In other embodiments W₂ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₂ is an oxidized N.

In some embodiments, - - - - - represents a bond. In some embodiments, aand c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In someembodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, t is 1.In some embodiments, Z is

and r is 2. In other embodiments, Z is

and s is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, Q is C(O)CH₃. In some embodiments, Q isZ. In some embodiments, Q is

In some embodiments, Q is

In some embodiments, T is H. In some embodiments, T is C(O)CH₃. In someembodiments, T is Z. In some embodiments, e is any one of the sidechains of the naturally occurring amino acids. In some embodiments, e isH.

In another aspect, compounds of the Formula Ia′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

r is 2 or 3;

s is 5 or 6;

each v is 1 or 2; and

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In some embodiments, R₂ is Cl or F. In other embodiments, R₃ is Cl or F.In some embodiments, r is 2. In some embodiments, r is 3. In someembodiments, s is 5. In some embodiments, s is 6. In some embodiments, tis 1. In some embodiments v is 2.

In another aspect compounds of the Formula Ib′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

R₁, R₂, R₃, R₄, R₁′, R₂′, R₃′, and R₄′ are each independently selectedfrom the group consisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H,—C(O)C₁-C₃ alkyl, —C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl),—C(O)N(C₁-C₃ alkyl)₂, —C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl,and —S(O)₂C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each of n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl; and

T is H, C(O)CH₃, or Z.

In some embodiments, R₂ is Cl or F. In other embodiments, R₃ is Cl or F.In some embodiments, W₁ is O. In some embodiments, W₂ is O. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —O CH₂CH₃, orC(O)OH; In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, t is 1. In some embodiments, Z is

and r is 2. In other embodiments, Z is

and s is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, T is H. In some embodiments, T isC(O)CH₃. In some embodiments, T is Z.

In another aspect compounds of the Formula Ic′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, enantiomers,and stereoisomers thereof,wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;W₁ and W₂ are each independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

n, o, p, and q are each independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2; and

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In some embodiments, R₂ is Cl or F. In other embodiments, R₃ is Cl or F.

In some embodiments, W₁ is O. In some embodiments, W₂ is O. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —O CH₂CH₃, orC(O)OH; In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, t is 1.In some embodiments, Z is

and r is 2. In other embodiments, Z is

and s is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6.

In another aspect, compounds of the Formula Id′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

n, o, p, and q are each independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2; and

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In some embodiments, R₂ is Cl or F. In other embodiments, R₃ is Cl or F.In some embodiments, W₁ is O. In some embodiments, W₂ is O. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —O CH₂CH₃, orC(O)OH; In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, Z is

and r is 2. In other embodiments, Z is

and s is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, t is 1. In some embodiments, T is H. Insome embodiments, T is C(O)CH₃. In some embodiments, T is Z.

In another aspect, compounds of the Formula Ie′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

each Z is independently H, —C(O)CH₃,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently s is 5 or 6; and

each t is independently 0 or 1

each v is 1 or 2; and

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In some embodiments, R₂ is Cl or F. In other embodiments, R₃ is Cl or F.In some embodiments, Z is

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, Z is

and r is 2. In other embodiments, Z is

and s is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, t is 1.

In another aspect, compounds of the Formula If′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

W₁ is O, or NH;

W₂ is null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In some embodiments, R₂ is Cl or F. In other embodiments, R₃ is Cl or F.In some embodiments, W₁ is O. In some embodiments, W₂ is O. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —O CH₂CH₃, orC(O)OH. In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, Z is

and r is 2. In other embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, t is 1.

In another aspect, compounds of the Formula Ig′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

W₃ is null, O, or NH;

e is H or any one of the side chains of the naturally occurring aminoacids;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl; and

s is 5 or 6.

In some embodiments, W₃ is O. In some embodiments, e is sec-butyl. Insome embodiments, r is 2. In some embodiments, r is 3. In someembodiments, s is 5. In some embodiments, s is 6. In some embodiments, tis 1.

In another aspect, compounds of the Formula II′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R₁, R₂, R₃, and R₄ are each independently selected from the groupconsisting of H, Cl, F, CN, NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂,—NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —C(O)H, —C(O)C₁-C₃ alkyl,—C(O)OC₁-C₃ alkyl, —C(O)NH₂, —C(O)NH(C₁-C₃ alkyl), —C(O)N(C₁-C₃ alkyl)₂,—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —S(O)C₁-C₃ alkyl, and —S(O)₂C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

- - - - - represents an optional bond that when present requires that Qis then null;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is 7;

each s is 3;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl;

Q is null, H, C(O)CH₃, Z,

e is H or any one of the side chains of the naturally occurring aminoacids;

W₃ is null, —O—, or —N(R)—;

R is H or C₁-C₃ alkyl; and

T is H, C(O)CH₃, or Z.

In some embodiments, R₂ is Cl or F. In other embodiments, R₃ is Cl or F.In some embodiments, W₁ is O. In some embodiments, W₂ is O.

In some embodiments, W₁ is N. In other embodiments W₁ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₁ is an oxidized N.

In some embodiments, W₂ is N. In other embodiments W₂ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₂ is an oxidized N.

In some embodiments, - - - - - represents a bond. In some embodiments, aand c are each independently H, CH₃, —OCH₃, —O CH₂CH₃, or C(O)OH. Insome embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 7. In some embodiments, Z is

and s is 3. In some embodiments, Z is

and r is 7. In some embodiments, Z is

and s is 3. In some embodiments, t is 1. In some embodiments, Q isC(O)CH₃. In some embodiments, Q is Z. In some embodiments, Q is

In some embodiments, Q is

In some embodiments, T is H. In some embodiments, T is C(O)CH₃. In someembodiments, T is Z. In some embodiments, e is any one of the sidechains of the naturally occurring amino acids. In some embodiments, e isH.

In another aspect, compounds of the Formula III′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

each W₁ and W₂ are independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

- - - - - represents an optional bond that when present requires that Qis null; each a and c are independently H, CH₃, —OCH₃, —OCH₂CH₃, orC(O)OH;

each b is H, CH₃, C(O)OH, or O—Z;

each d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2, 3, or 7;

each s is independently 3, 5, or 6;

each t is independently 0 or 1;

each v is 1 or 2;

each R₅ and R₆ are independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl;

u is 0 or 1;

with the proviso that when r is 7, s is 3;

Q is null, C(O)CH₃, Z,

e is H or any one of the side chains of the naturally occurring aminoacids;

W₃ is null, —O—, or —N(R)—;

R is H or C₁-C₃ alkyl; and

T is H, C(O)CH₃, or Z.

In some embodiments, W₁ is O. In some embodiments, W₂ is O.

In some embodiments, W₁ is N. In other embodiments W₁ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₁ is an oxidized N.

In some embodiments, W₂ is N. In other embodiments W₂ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₂ is an oxidized N.

In some embodiments, - - - - - represents a bond. In some embodiments, aand c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In someembodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, Z is

and r is 2. In other embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, t is 1. In some embodiments, Q isC(O)CH₃. In some embodiments, Q is Z. In some embodiments, Q is

In some embodiments, Q is

In some embodiments, T is H. In some embodiments, T is C(O)CH₃. In someembodiments, T is Z. In some embodiments, e is any one of the sidechains of the naturally occurring amino acids. In some embodiments, e isH.

In yet another aspect, compounds of the Formula IIIa′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

each W₁ and W₂ are independently null, O, or NH, or when W₁ and W₂ areboth NH, then both W₁ and W₂ can be taken together to form a piperidinemoiety;

- - - - - represents an optional bond that when present requires that Qis null;

each a and c are independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

each b is H, CH₃, C(O)OH, or O—Z;

each d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2, 3, or 7;

each s is independently 3, 5, or 6;

each t is independently 0 or 1;

each v is 1 or 2;

each R₅ and R₆ are independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl;

u is 0 or 1;

with the proviso that when r is 7, s is 3;

Q is null, C(O)CH₃, Z,

e is H or any one of the side chains of the naturally occurring aminoacids;

W₃ is null, —O—, or —N(R)—;

R is H or C₁-C₃ alkyl; and

T is H, C(O)CH₃, or Z.

In some embodiments, W₁ is O. In some embodiments, W₂ is O. In someembodiments, - - - - - represents a bond. In some embodiments, a and care each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In someembodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, Z is

and r is 2. In other embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, t is 1. In some embodiments, Q isC(O)CH₃. In some embodiments, Q is Z. In some embodiments, Q is

In some embodiments, W₃ is O. In other embodiments, W₃ is N(R). Infurther embodiments, W₃ is NH. In some embodiments, e is any one of theside chains of the naturally occurring amino acids. In some embodiments,e is H.

In some embodiments, Q is

In some embodiments, T is H. In some embodiments, T is C(O)CH₃. In someembodiments, T is Z. In some embodiments, e is any one of the sidechains of the naturally occurring amino acids. In some embodiments, e isH.

In another aspect, compounds of Formula IV′ are described herein:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

W₁ and W₂ are each independently null, O, or NH;

- - - - - represents an optional bond that when present requires that Qis null;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl;

Q is null, C(O)CH₃, Z, or

e is H, —C(O)OH, or any one of the side chains of the naturallyoccurring amino acids;

W₃ is null, —O—, —N(R)—; and

R is H or C₁-C₃ alkyl.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH.

In some embodiments, W₁ is N. In other embodiments W₁ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₁ is an oxidized N.

In some embodiments, W₂ is N. In other embodiments W₂ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₂ is an oxidized N.

In some embodiments, - - - - - represents a bond. In some embodiments, aand c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In someembodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, Z is

and r is 2. In other embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, t is 1. In some embodiments, Q is H. Inother embodiments, Q is C(O)CH₃. In some embodiments, Q is Z. In someembodiments, Q is

In some embodiments, e is any one of the side chains of the naturallyoccurring amino acids. In some embodiments, e is H. In otherembodiments, e is —C(O)OH. In some embodiments, W₃—NH—. In someembodiments, W₃ is O.

In another aspect, compounds of the Formula IVa′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl; and

s is 5 or 6.

In some embodiments, r is 2. In some embodiments, r is 3. In someembodiments, s is 5. In some embodiments, s is 6.

In another aspect, compounds of the Formula IVb′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, enantiomers,and stereoisomers thereof,wherein

W₁ and W₂ are each independently null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, orC(O)OH; In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0.

In some embodiments, Z is

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, Z is

and r is 2. In other embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, Z is not H. In some embodiments, t is1.

In another aspect, compounds of the Formula IVc′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

W₁ and W₂ are each independently null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each of n, o, p, and q is independently 0 or 1;

each Z is null, H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —O CH₂CH₃, orC(O)OH; In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, Z is

and r is 2. In other embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, at most one Z is H. In someembodiments, Z is not H. In other embodiments, Z is not —C(O)CH₃. Insome embodiments, t is 1.

In another aspect, compounds of the Formula IVd′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

each Z is null, H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In some embodiments, Z is

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, Z is

and r is 2. In other embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, t is 1.

In another aspect, compounds of the Formula IVe′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

W₁ is O, or NH;

W₂ is null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, orC(O)OH. In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, Z is

and r is 2. In other embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, t is 1.

In another aspect, compounds of the Formula IVf′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

e is H, —C(O)OH or any one of the side chains of the naturally occurringamino acids;

W₃ is null, —O—, —N(R)—; and

R is H or C₁-C₃ alkyl,

v is 1 or 2;

s is 5 or 6; and

t is 0 or 1.

In some embodiments, W₃ is O. In some embodiments, e is sec-butyl. Inother embodiments, e is —C(O)OH. In still other embodiments, e is H. Insome embodiments, W₃ is —NR—. In some embodiments. In some embodiments,r is 2. In some embodiments, r is 3. In some embodiments, s is 5. Insome embodiments, s is 6. In some embodiments, v is 1. In otherembodiments, v is 2. In some embodiments, t is 1.

In another aspect, compounds of the Formula IVg′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R is H or C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —O CH₂CH₃, orC(O)OH; In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, Z is

and r is 2. In other embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, at most one Z is H. In someembodiments, Z is not H. In other embodiments, Z is not —C(O)CH₃. Insome embodiments, t is 1.

In still another aspect, compounds of the Formula V′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

W₁ and W₂ are each independently null, O, or NH;

- - - - - represents an optional bond that when present requires that Qis then null;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is independently null, H,

with the proviso that there is at least one

in the compound;

each r is independently 7;

each s is independently 3;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl;

Q is null, C(O)CH₃, Z, or

and

e is H, —C(O)OH or any one of the side chains of the naturally occurringamino acids.

In some embodiments, W₁ is O. In some embodiments, W₁ is NH. In someembodiments, W₂ is O. In some embodiments, W₂ is NH.

In some embodiments, W₁ is N. In other embodiments W₁ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₁ is an oxidized N.

In some embodiments, W₂ is N. In other embodiments W₂ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₂ is an oxidized N.

In some embodiments, - - - - - represents a bond. In some embodiments, aand c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In someembodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 7. In some embodiments, Z is

and s is 3. In some embodiments, Z is

and r is 7. In other embodiments, Z is

and s is 3. In some embodiments, t is 1. In some embodiments, Q isC(O)CH₃, In some embodiments, Q is Z. In some embodiments, Q is

In some embodiments, e is any one of the side chains of the naturallyoccurring amino acids. In some embodiments, e is H. In otherembodiments, e is —C(O)OH. In some embodiments, W₃—NR—. In someembodiments, W₃ is O.

In yet another aspect, compounds of the Formula VI′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

W₁ and W₂ are each independently null, O, or NH;

- - - - - represents an optional bond that when present requires that Qis null;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 0, 1, 2, or 3;

each s is independently an integer from 1 to 10;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl;

Q is null, C(O)CH₃, Z, or

e is H, —C(O)OH, or any one of the side chains of the naturallyoccurring amino acids;

W₃ is null, —O—, —N(R)—; and

R is H or C₁-C₃ alkyl.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH.

In some embodiments, W₁ is N. In other embodiments W₁ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₁ is an oxidized N.

In some embodiments, W₂ is N. In other embodiments W₂ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₂ is an oxidized N.

In some embodiments, - - - - - represents a bond. In some embodiments, aand c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In someembodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, Z is

and r is 2. In other embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, t is 1. In some embodiments, Q is H. Inother embodiments, Q is C(O)CH₃. In some embodiments, Q is Z. In someembodiments, Q is

In some embodiments, e is any one of the side chains of the naturallyoccurring amino acids. In some embodiments, e is H. In otherembodiments, e is —C(O)OH. In some embodiments, W₃ is —NR—. In someembodiments, W₃ is O.

In another aspect, compounds of the Formula VIa′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl; and

s is independently 5 or 6.

In some embodiments, r is 2. In some embodiments, r is 3. In someembodiments, s is 5. In some embodiments, s is 6.

In another aspect, compounds of the Formula VIb′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, enantiomers,and stereoisomers thereof,wherein

W₁ and W₂ are each independently null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, orC(O)OH; In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0.

In some embodiments, Z is

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, Z is

and r is 2. In other embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, Z is not H. In some embodiments, t is1.

In another aspect, compounds of the Formula VIc′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

W₁ and W₂ are each independently null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each of n, o, p, and q is independently 0 or 1;

each Z is independently null, H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —O CH₂CH₃, orC(O)OH; In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1.

In some embodiments, n is 0. In some embodiments, Z is

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, Z is

and r is 2. In other embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, at most one Z is H. In someembodiments, Z is not H.

In other embodiments, Z is not —C(O)CH₃. In some embodiments, t is 1.

In another aspect, compounds of the Formula VId′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

each Z is independently H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In some embodiments, Z is

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, Z is

and r is 2. In other embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, t is 1.

In another aspect, compounds of the Formula VIe′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

W₁ is O, or NH;

W₂ is null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is

independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, orC(O)OH. In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1. In some embodiments, n is 0. In some embodiments, Zis

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, Z is

and r is 2. In other embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, t is 1.

In another aspect, compounds of the Formula VIP are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;wherein

e is H, —C(O)OH or any one of the side chains of the naturally occurringamino acids;

W₃ is null, —O—, —N(R) and

R is H or C₁-C₃ alkyl,

each v is 1 or 2;

each R₅ and R₆ are independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl; and

s is 5 or 6.

In some embodiments, W₃ is O. In some embodiments, e is sec-butyl. Inother embodiments, e is —C(O)OH. In still other embodiments, e is H. Insome embodiments, W₃ is —NR—. In some embodiments, W₃ is O. In someembodiments, r is 2. In some embodiments, r is 3. In some embodiments, sis 5. In some embodiments, s is 6. In some embodiments, t is 1.

In another aspect, compounds of the Formula VIg′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

R is H or C₁-C₃ alkyl;

W₁ and W₂ are each independently null, O, or NH;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 2 or 3;

each s is independently 5 or 6;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl.

In some embodiments, W₁ is O. In other embodiments, W₁ is NH. In someembodiments, W₂ is O. In other embodiments, W₂ is NH. In someembodiments, a and c are each independently H, CH₃, —OCH₃, —O CH₂CH₃, orC(O)OH; In some embodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1.

In some embodiments, n is 0. In some embodiments, Z is

and r is 2. In some embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In some embodiments, Z is

and s is 6. In some embodiments, Z is

and r is 2. In other embodiments, Z is

and r is 3. In some embodiments, Z is

and s is 5. In other embodiments, Z is

and s is 6. In some embodiments, at most one Z is H. In someembodiments, Z is not H. In other embodiments, Z is not —C(O)CH₃. Insome embodiments, t is 1.

In another aspect, compounds of the Formula VII′ are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

wherein

W₁ and W₂ are each independently null, O, or NH;

- - - - - represents an optional bond that when present requires that Qis then null;

a and c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH;

b is H, CH₃, C(O)OH, or O—Z;

d is H or C(O)OH;

each n, o, p, and q is independently 0 or 1;

each Z is H,

with the proviso that there is at least one

in the compound;

each r is independently 7;

each s is independently 3;

each t is independently 0 or 1;

each v is 1 or 2;

R₅ and R₆ are each independently hydrogen, deuterium, C₁-C₄ alkyl,halogen, —OH, —C(O)C₁-C₄ alkyl, —O-aryl, —O-benzyl, —OC(O)C₁-C₄ alkyl,—C₁-C₃ alkene, —C₁-C₃ alkyne, —C(O)C₁-C₄ alkyl, NH₂, —NH(C₁-C₃ alkyl),—N(C₁-C₃ alkyl)₂, —NH(C(O)C₁-C₃ alkyl), —N(C(O)C₁-C₃ alkyl)₂, —SH,—S(C₁-C₃ alkyl), —S(O)C₁-C₃ alkyl, —S(O)₂C₁-C₃ alkyl;

Q is null, C(O)CH₃, Z, or

W₃ is null, —O—, —N(R)—;

R is H or C₁-C₃ alkyl; and

e is H, —C(O)OH or any one of the side chains of the naturally occurringamino acids.

In some embodiments, W₁ is O. In some embodiments, W₁ is NH. In someembodiments, W₂ is O. In some embodiments, W₂ is NH.

In some embodiments, W₁ is N. In other embodiments W₁ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₁ is an oxidized N.

In some embodiments, W₂ is N. In other embodiments W₂ is N substitutedwith a C₁-C₆ alkyl. In other embodiments, W₂ is an oxidized N.

In some embodiments, - - - - - represents a bond. In some embodiments, aand c are each independently H, CH₃, —OCH₃, —OCH₂CH₃, or C(O)OH. In someembodiments, b is O—Z, Z is

and t is 1. In some embodiments, d is C(O)OH. In some embodiments n, o,p, and q are each 1.

In some embodiments, n is 0. In some embodiments, Z is

and r is 7. In some embodiments, Z is

and s is 3. In some embodiments, Z is

and r is 7. In other embodiments, Z is

and s is 3. In some embodiments, t is 1. In some embodiments, Q isC(O)CH₃, In some embodiments, Q is Z. In some embodiments, Q is

In some embodiments, e is any one of the side chains of the naturallyoccurring amino acids. In some embodiments, e is H. In otherembodiments, e is —C(O)OH. In some embodiments, W₃ is —NR—. In someembodiments, W₃ is O.

In any of the above Formulae, any one or more of H may be substitutedwith a deuterium. It is also understood in any of the above Formulaethat a methyl subtituent can be substituted with a C₁-C₆ alkyl.

Methods for Using Compounds of the Invention

The invention also includes methods for upregulating ananti-inflammatory pathway and downregulating a proinflammatory pathwayin a cell.

In one embodiment, the method comprises contacting a cell with aCompound of the Invention in an amount sufficient to upregulate ananti-inflammatory pathway and down regulate a proinflammatory pathway inthe cell. In general, any cell having, or capable of having,inflammatory activity or capable of expressing NFκB can be used. Thecell can be provided in any form. For example, the cell can be providedin vitro, ex vivo, or in vivo. Inflammatory activity can be measuredusing any method known in the art, e.g., methods as described in Tran P.O., et al., Diabetes, 51; 1772-8, 2002. Illustrative examples of cellscapable of inflammatory activity include, but are not limited to, immunecells including monocytes, macrophages, T-cell, Th-1, Th-2, Th-17, Treg,lymphocytes, spleen cells, muscle, adipose or fat, vascular cells suchas endothelial or pericyte, bone, gum, nerve, brain, glial, astrocytes,nerve, liver, kidney, pancreas including islet cells such as beta cells,lung, heart, breast, bladder, stomach, colon, rectal, small intestine,skin, esophageal, eye, larynx, uterine, ovarian, prostate, tendon, bonemarrow, blood, lymph, testicular, vaginal and neoplastic cells.

Also provided in the invention is a method for inhibiting, preventing,or treating inflammation or an inflammatory disease in a subject. Theinflammation can be associated with an inflammatory disease or a diseasewhere inflammation contributes to the disease. Inflammatory diseases canarise where there is an inflammation of the body tissue. These includelocal inflammatory responses and systemic inflammation. Examples of suchdiseases include, but are not limited to: organ transplant rejection;reoxygenation injury resulting from organ transplantation (see Grupp etal., J. Mol. Cell. Cardiol. 31: 297-303 (1999)) including, but notlimited to, transplantation of the following organs: heart, lung, liverand kidney; chronic inflammatory diseases of the joints, includingarthritis, rheumatoid arthritis, osteoarthritis and bone diseasesassociated with increased bone resorption; inflammatory bowel diseasessuch as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn'sdisease; inflammatory lung diseases such as asthma, adult respiratorydistress syndrome, chronic obstructive airway disease, and cysticfibrosis; inflammatory diseases of the eye including corneal dystrophy,trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis andendophthalmitis; chronic inflammatory diseases of the gum, includinggingivitis and periodontitis; inflammatory diseases of the kidneyincluding uremic complications, glomerulonephritis and nephrosis;inflammatory diseases of the skin including sclerodermatitis, psoriasisand eczema; inflammatory diseases of the central nervous system,including chronic demyelinating diseases of the nervous system, multiplesclerosis, AIDS-related neurodegeneration and Alzheimer's disease,infectious meningitis, encephalomyelitis, Parkinson's disease,Huntington's disease, amyotrophic lateral sclerosis and viral orautoimmune encephalitis. Metabolic disease such as type II diabetesmellitus; the prevention of type I diabetes; dyslipedemia;hypertriglyceridemia; diabetic complications, including, but not limitedto glaucoma, retinopathy, macula edema, nephropathy, such asmicroalbuminuria and progressive diabetic nephropathy, polyneuropathy,diabetic neuropathy, atherosclerotic coronary arterial disease,peripheral arterial disease, nonketotic hyperglycemichyperosmolar coma,mononeuropathies, autonomic neuropathy, joint problems, and a skin ormucous membrane complication, such as an infection, a shin spot, acandidal infection or necrobiosis lipoidica diabeticorum; immune-complexvasculitis, systemic lupus erythematosus; inflammatory diseases of theheart such as cardiomyopathy, ischemic heart diseasehypercholesterolemia, and atherosclerosis; as well as various otherdiseases that can have significant inflammatory components, includingpreeclampsia; chronic liver failure, brain and spinal cord trauma, andcancer. The inflammatory disease can also be a systemic inflammation ofthe body, exemplified by gram-positive or gram negative shock,hemorrhagic or anaphylactic shock, or shock induced by cancerchemotherapy in response to proinflammatory cytokines, e.g., shockassociated with proinflammatory cytokines Such shock can be induced,e.g., by a chemotherapeutic agent that is administered as a treatmentfor cancer. Other disorders include depression, obesity, allergicdiseases, acute cardiovascular events, arrhythmia, prevention of suddendeath, muscle wasting diseases such as Duchenne′s Muscular Dystrophy,inflammatory myopathies such as dermatomositis, inclusion body myositis,and polymyositis, and cancer cachexia. Also inflammation that resultsfrom surgery and trauma can be treated with Compound of the Invention.

In some embodiments, the subject is administered an effective amount ofa Compound of the Invention.

The invention also includes pharmaceutical compositions useful fortreating or preventing an inflammatory disease, or for inhibitinginflammation activity, or more than one of these activities. Thecompositions can be suitable for internal use and comprise an effectiveamount of a Compound of the Invention and a pharmaceutically acceptablecarrier. The Compounds of the Invention are especially useful in thatthey demonstrate very low peripheral toxicity or no peripheral toxicity.

The Compounds of the Invention can each be administered in amounts thatare sufficient to treat or prevent an inflammatory disease or areperfusion disease and/or prevent the development thereof in subjects.

Administration of the Compounds of the Invention can be accomplished viaany mode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the compositions canbe in solid, semi-solid or liquid dosage form, such as, for example,injectables, tablets, suppositories, pills, time-release capsules,elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, orthe like, sometimes in unit dosages and consistent with conventionalpharmaceutical practices. Likewise, they can also be administered inintravenous (both bolus and infusion), intraperitoneal, subcutaneous orintramuscular form, all using forms well known to those skilled in thepharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a Compound of the Invention and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, algiic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the Compound ofthe Invention is dissolved in or mixed with a pharmaceuticallyacceptable solvent such as, for example, water, saline, aqueousdextrose, glycerol, ethanol, and the like, to thereby form an injectableisotonic solution or suspension. Proteins such as albumin, chylomicronparticles, or serum proteins can be used to solubilize the Compounds ofthe Invention.

The Compounds of the Invention can be also formulated as a suppositorythat can be prepared from fatty emulsions or suspensions; usingpolyalkylene glycols such as propylene glycol, as the carrier.

The Compounds of the Invention can also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564.

Compounds of the Invention can also be delivered by the use ofmonoclonal antibodies as individual carriers to which the Compounds ofthe Invention are coupled. The Compounds of the Invention can also becoupled with soluble polymers as targetable drug carriers. Such polymerscan include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the Compounds of theInvention can be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels. In one embodiment, Compoundsof the Invention are not covalently bound to a polymer, e.g., apolycarboxylic acid polymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of theCompound of the Invention by weight or volume.

The dosage regimen utilizing the Compound of the Invention is selectedin accordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular Compound of theInvention employed. A physician or veterinarian of ordinary skill in theart can readily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the present invention, when used for theindicated effects, range from about 20 mg to about 5000 mg of theCompound of the Invention per day. Compositions for in vivo or in vitrouse can contain about 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250,2500, 3500, or 5000 mg of the Compound of the Invention. In oneembodiment, the compositions are in the form of a tablet that can bescored. Effective plasma levels of the Compound of the Invention canrange from about 0.002 mg to about 100 mg per kg of body weight per day.Appropriate dosages of the Compounds of the Invention can be determinedas set forth in L. S. Goodman, et al., The Pharmacological Basis ofTherapeutics, 201-26 (5th ed. 1975).

Compounds of the Invention can be administered in a single daily dose,or the total daily dosage can be administered in divided doses of two,three or four times daily. Furthermore, Compounds of the Invention canbe administered in intranasal form via topical use of suitableintranasal vehicles, or via transdermal routes, using those forms oftransdermal skin patches well known to those of ordinary skill in thatart. To be administered in the form of a transdermal delivery system,the dosage administration can be continuous rather than intermittentthroughout the dosage regimen. Other illustrative topical preparationsinclude creams, ointments, lotions, aerosol sprays and gels, wherein theconcentration of the Compound of the Invention ranges from about 0.1% toabout 15%, w/w or w/v.

Methods for Making the Fatty Acid Acetylated Salicylate Derivatives

Examples of synthetic pathways useful for making Fatty Acid AcetylatedSalicylate Derivatives of Formula I, Formula Ia, Formula Ib, Formula Ic,Formula Id, Formula Ie, Formula If, Formula Ig, and Formula II are setforth in the Examples below and generalized in Schemes 1-4.

wherein r and s are as defined above for Formula I, Formula Ia, FormulaIb, Formula Ic, Formula Id, Formula Ie, Formula If, Formula Ig, andFormula II.

Compound A can be esterified in the presence of acid catalyst and asuitable alcohol, e.g., ethanol to give ester B. Activation of compoundB with a coupling reagent such as for example DCC, CDI, or EDC,optionally with a tertiary amine base and/or catalyst, e.g., DMAP,followed by addition of a fatty acid of Formula C affords compounds ofFormula D. Alternatively, compound A can be esterified with benzylbromide in the presence of base, e.g., CsCO₃, then subjected to theremaining steps of Scheme 1. Hydrogenolysis of the benzyl ester derivedfrom A, for example using Pd/C and H2, can yield the free acid ofcompounds of Formula D.

wherein r and s are as defined above for compounds of Formula I, FormulaIa, Formula Ib, Formula Ic, Formula Id, Formula Ie, Formula If, FormulaIg, Formula II, and Formula III.

Compound A can be esterified in the presence of acid catalyst and asuitable protecting alcohol such as, e.g., t-butanol, followed bycoupling to an activated amino acid to give compound F. Condensation ofthe amino compound F with a fatty acid chloride of Formula G affordscompounds of Formula H. The ester may be deprotected using methodsdisclosed in Greene, et al. Protecting Groups in Organic Chemistry.4^(th) ed. Wiley & Sons, Hoboken, N.J. (2007). See, e.g., Chapter 5,therein.

wherein r and s are as defined above for Formula I, Formula Ia, FormulaIb, Formula Ic, Formula Id, Formula Ie, Formula If, Formula Ig, andFormula II.

Acid I can be activated by esterification with a suitable activatingagent such as, e.g., pivoyl chloride, followed by condensation with anamino alcohol such as for example n-propanolamine, to give compound K.Condensation of the alcohol compound K with a fatty acid chloride ofFormula G affords compounds of Formula L. Diacylated compounds of theinvention can be made by subjecting compound A to the above procedure.

wherein r and s are as defined above for Formula I, Formula Ia, FormulaIb, Formula Ic, Formula Id, Formula Ie, Formula If, Formula Ig, andFormula II.

Activated ester J (see Scheme 3) can be condensed with an amino-maskeddiol M, which after acid workup gives the unmasked diol compound N.Condensation of the diol compound N with a fatty acid chloride ofFormula G affords compounds of Formula O.

Methods for Making the Fatty Acid Acetylated Diflunisal Derivatives

Examples of synthetic pathways useful for making Fatty Acid AcetylatedDiflunisal Derivatives of Formula IV, Formula IVa, Formula IVb, FormulaIVc, Formula IVd, Formula IVe, Formula IVf, Formula IVg, and Formula V,are set forth herein and generalized in Schemes 5-9.

wherein r and s are as defined for Formula IV, Formula IVa, Formula IVb,Formula IVc, Formula IVd, Formula IVe, Formula IVf, Formula IVg, andFormula V.

Compound P can be esterified in the presence of acid catalyst and asuitable alcohol, e.g., ethanol to give ester Q. Activation of compoundQ with a coupling reagent such as for example DCC, CDI, or EDC,optionally with a tertiary amine base and/or catalyst, e.g., DMAP,followed by addition of a fatty acid of Formula C affords compounds ofFormula R. Alternatively, compound P can be esterified with benzylbromide in the presence of base, e.g., CsCO₃, then subjected to theremaining steps of Scheme 5. Hydrogenolysis of the benzyl ester derivedfrom P, for example using Pd/C and H2, can yield the free acid ofcompounds of Formula R.

wherein r and s are as defined for Formula IV, Formula IVa, Formula IVb,Formula IVc, Formula IVd, Formula IVe, Formula IVf, Formula IVg, andFormula V.

Compound P can be esterified in the presence of acid catalyst and asuitable protecting alcohol such as, e.g., t-butanol, followed bycoupling to an activated amino acid to give compound S. Condensation ofthe amino compound S with a fatty acid chloride of Formula G affordscompounds of Formula T. The ester may be deprotected using methodsdisclosed in Greene, et al. Protecting Groups in Organic Chemistry.4^(th) ed. Wiley & Sons, Hoboken, N.J. (2007). See, e.g., Chapter 5,therein.

wherein r and s are as defined above for Formula IV, Formula IVa,Formula IVb, Formula IVc, Formula IVd, Formula IVe, Formula IVf, FormulaIVg, and Formula V.

Acid U can be activated by esterification with a suitable activatingagent such as, e.g., pivoyl chloride, followed by condensation with anamino alcohol such as for example n-propanolamine, to give compound W.Condensation of the alcohol compound W with a fatty acid chloride ofFormula G affords compounds of Formula X. Diacylated compounds of theinvention can be made by subjecting compound P to the above procedure.

wherein r and s are as defined above for Formula IV, Formula IVa,Formula IVb, Formula IVc, Formula IVd, Formula IVe, Formula IVf, FormulaIVg, and Formula V.

Activated ester V (see Scheme 7) can be condensed with a amino-maskeddiol M, which after acid workup gives the unmasked diol compound Z.Condensation of the diol compound Z with a fatty acid chloride ofFormula G affords compounds of Formula AA.

wherein r and s are as defined for Formula IV, Formula IVa, Formula IVb,Formula IVc, Formula IVd, Formula IVe, Formula IVf, Formula IVg, andFormula V.

Compound P can be esterified with benzyl bromide in the presence of abase, e.g. CsCO₃ yielding compound BB. Condensation of compound BB witha fatty acid chloride of Formula G affords compounds of Formula CC.Hydrogenolysis of the benzyl ester of compounds of Formula CC, e.g.using Pd/C and H₂, yields compounds of Formula DD.

Methods for Making the Fatty Acid Acetylated Triflusal Derivatives

Examples of synthetic pathways useful for making Fatty Acid AcetylatedTriflusal Derivatives of Formula VI, Formula VIa, Formula VIb, FormulaVIc, Formula VId, Formula VIe, Formula VIf, Formula VIg, and FormulaVII, are set forth herein and generalized in Schemes 10-14.

wherein r and s are as defined above for Formula VI, Formula VIa,Formula VIb, Formula VIc, Formula VId, Formula VIe, Formula VIf, FormulaVIg, and Formula VII.

Compound EE can be esterified in the presence of acid catalyst and asuitable alcohol, e.g., ethanol to give ester FF. Activation of compoundFF with a coupling reagent such as for example DCC, CDI, or EDC,optionally with a tertiary amine base and/or catalyst, e.g., DMAP,followed by addition of a fatty acid of Formula C affords compounds ofFormula GG.

Alternatively, compound EE can be esterified with benzyl bromide in thepresence of base, e.g., CsCO₃, then subjected to the remaining steps ofScheme 1. Hydrogenolysis of the benzyl ester derived from EE, forexample using Pd/C and H₂, can yield the free acid of compounds ofFormula GG.

wherein r, s and u can be as described for Formula VI, Formula VIa,Formula VIb, Formula VIc, Formula VId, Formula VIe, Formula VIf, FormulaVIg, and Formula VII.

Compound EE can be esterified in the presence of acid catalyst and asuitable protecting alcohol such as, e.g., t-butanol, followed bycoupling to an activated amino acid to give compound HH. Condensation ofthe amino compound HH with a fatty acid chloride of Formula G affordscompounds of Formula JJ. The ester may be deprotected using methodsdisclosed in Greene, et al. Protecting Groups in Organic Chemistry.4^(th) ed. Wiley & Sons, Hoboken, N.J. (2007). See, e.g., Chapter 5,therein.

wherein r and s are as defined above for Formula VI, Formula VIa,Formula VIb, Formula VIc, Formula VId, Formula VIe, Formula VIf, FormulaVIg, and Formula VII.

Acid KK can be activated by esterification with a suitable activatingagent such as, e.g., pivoyl chloride, followed by condensation with anamino alcohol such as for example n-propanolamine, to give compound MM.Condensation of the alcohol compound MM with a fatty acid chloride ofFormula G affords compounds of Formula NN. Diacylated compounds of theinvention can be made by subjecting compound EE to the above procedure.

wherein r and s are as defined above for Formula VI, Formula VIa,Formula VIb, Formula VIc, Formula VId, Formula VIe, Formula VIf, FormulaVIg, and Formula VII.

Activated ester LL (see Scheme 12) can be condensed with a amino-maskeddiol M, which after acid workup gives the unmasked diol compound OO.Condensation of the diol compound OO with a fatty acid chloride ofFormula G affords compounds of Formula PP.

wherein r and s are as defined above for Formula VI, Formula VIa,Formula VIb, Formula VIc, Formula VId, Formula VIe, Formula VIf, FormulaVIg, and Formula VII.

Compound EE can be esterified with benzyl bromide in the presence of abase, e.g. CsCO₃ yielding compound QQ. Condensation of compound QQ witha fatty acid chloride of Formula G affords compounds of Formula RR.Hydrogenolysis of the benzyl ester of compounds of Formula RR, e.g.using Pd/C and H₂, yields compounds of Formula SS.

Methods for Making the Fatty Acid Acetylated Amino SalicylateDerivatives

Examples of synthetic pathways useful for making Fatty Acid AcetylatedAmino Salicylate Derivatives of Formula III are set forth in theExamples below and generalized in Schemes 15-18.

wherein r and s are as defined for Formula III.

Compound TT can be esterified in the presence of acid catalyst and asuitable alcohol, e.g., methanol to give ester UU. Activation ofcompound UU with a coupling reagent such as for example DCC, CDI, orEDC, optionally with a tertiary amine base and/or catalyst, e.g., DMAP,followed by addition of a fatty acid of Formula C affords compounds ofFormula VV. Saponification of the esters of Formula VV with a suitablebase, such as for example NaOH, can yield the free acid of compounds ofFormula VV. Alternatively, compound TT can be esterified with benzylbromide in the presence of base, e.g., CsCO₃, then subjected to theremaining steps of Scheme 1. Hydrogenolysis of the benzyl ester derivedfrom TT, for example using Pd/C and H₂, can yield the free acid ofcompounds of Formula VV. Diacylated compounds of the invention can bemade by subjecting compound TT to the above procedure.

wherein r and s are as defined for Formula III.

Isocyanide WW can be condensed with an amino-masked ethanolamine XX,which after acid workup gives the unmasked aminocarbamate compound YY.Activation of compound YY with a coupling reagent such as for exampleDCC, CDI, or EDC, optionally with a tertiary amine base and/or catalyst,e.g., DMAP, followed by addition of a fatty acid of Formula C affordscompounds of Formula ZZ. The ester may be deprotected using methodsdisclosed in Greene, et al. Protecting Groups in Organic Chemistry.4^(th) ed. Wiley & Sons, Hoboken, N.J. (2007). See, e.g., Chapter 5,therein.

wherein r and s are as defined for Formula III.

Isocyanide WW can be condensed with an mono amino-masked ethylenediamineAAA, which after acid workup gives the unmasked urea compound BBB.Activation of compound BBB with a coupling reagent such as for exampleDCC, CDI, or EDC, optionally with a tertiary amine base and/or catalyst,e.g., DMAP, followed by addition of a fatty acid of Formula C affordscompounds of Formula CCC. The ester may be deprotected using methodsdisclosed in Greene, et al. Protecting Groups in Organic Chemistry.4^(th) ed. Wiley & Sons, Hoboken, N.J. (2007). See, e.g., Chapter 5,therein.

wherein r and s are as defined for Formula III.

Compound TT can be esterified in the presence of acid catalyst and asuitable protecting alcohol such as, e.g., methanol, followed bycoupling to an activated amino acid to give compound DDD. Condensationof the amino compound DDD with a fatty acid chloride of Formula Gaffords compounds of Formula EEE. The ester may be deprotected usingmethods disclosed in Greene, et al. Protecting Groups in OrganicChemistry. 4^(th) ed. Wiley & Sons, Hoboken, N.J. (2007). See, e.g.,Chapter 5, therein.

7. EXAMPLES

The disclosure is further illustrated by the following examples, whichare not to be construed as limiting this disclosure in scope or spiritto the specific procedures herein described. It is to be understood thatthe examples are provided to illustrate certain embodiments and that nolimitation to the scope of the disclosure is intended thereby. It is tobe further understood that resort may be had to various otherembodiments, modifications, and equivalents thereof which may suggestthemselves to those skilled in the art without departing from the spiritof the present disclosure and/or scope of the appended claims.

Example 1 Effect of Illustrative Compounds of the Invention onInflammatory Activity in Adipose Tissue in Mice

Demonstration of the ability of illustrative Compounds of the Inventionto mediate serum adiponectin concentrations in a rodent obesity modelwas shown using methods described in Itoh, M., et al., Arterioscler.Thromb. Vasc. Biol. 2007 27(9):1918-25. Male C57BL/6J ob/ob mice andtheir wild-type (WT) littermates are purchased from Charles RiverLaboratories (Wilmington, Mass.). The animals are housed in individualcages in a temperature-, humidity-, and light-controlled room (12-hourlight and 12-hour dark cycle) and allowed free access to water and fishmeal-free diet (fish meal-free F1 (Funabashi Farm, Chiba, Japan)supplemented with; 362 kcal/100 g, 4.4% energy as fat).

Six-week-old male ob/ob mice and WT littermates are allowed unrestrictedaccess to the fish meal-free diet (control group) or fish meal-free dietsupplemented with 5% EPA (wt/wt) (EPA-treated group) for 4 weeks (n=10to 14). In the short-term administration protocol, 8-week-old male ob/obmice are treated with the Compound of the Invention for 2 weeks (n=7 to8). All diets are changed every day and served with nonmetallic feederto prevent oxidization of fatty acids. At the end of the experiments,mice are euthanized after 5-hour starvation under intraperitonealpentobarbital anesthesia (30 mg/kg). Blood glucose and serumconcentrations of triglyceride (TG) and free fatty acid (FFA) aremeasured as described in Kouyama R, et al., Endocrinology, 146:3481-3489, 2005. Serum fatty acid and salicylate concentrations aremeasured by gas chromatography.

Example 2 In Vivo Effects of Compounds of the Invention in Zucker FattyRats and ob/ob Mice

Twelve-week-old male Zucker fa/fa rats and 8-week-old ob/ob (Lepob/ob)and ob/1 mice are given free access to food and water. A Compound of theInvention (120 mg/kg/day) is dosed orally by gavage once per day. Forglucose tolerance tests, glucose (2.0 g/kg) is administered by oralgavage (rats) or intraperitoneal injection (mice) after an overnightfast. Blood glucose and serum insulin concentrations are determinedduring oral glucose tolerance tests in Zucker fa/fa rats or fa/1 rats.For insulin tolerance tests, insulin (2.0 U/kg) is injectedintraperitoneally after an overnight fast. Cholesterol, triglyceride,long-chain FFA, and ALT concentrations are measured in sera from fastingZucker fa/fa rats.

Example 3 Effects of Compounds of the Invention on Insulin Signaling in3T3-L1 Adipocytes

3T3-L1 adipocytes are serum starved for 16 hours and treated or nottreated with 5 mM aspirin for 2 hours and either 6.0 nM mTNFα (20 min)or the phosphatasen inhibitor calyculin A (Axxora, San Diego, USA) (at2.0 nM for 30 min) as described in Yuan, M., et al., Science, 293,1673-1677, 2001. After a 5-min stimulation with 10 nM insulin, the cellsare chilled and solubilized and proteins are immunoprecipitated withanti-IR or anti-IRS1. Proteins are separated by SDS-PAGE and identifiedby Western blotting with anti-pY, anti-IR, or anti-IRS1.

Example 4 Effects of Compounds of the Invention on IL-10 Levels in3T3-L1 Adipocytes

IL-10 production in 3T3-L1 adipocytes is measured using a modificationof the method described by Bradley et al, Obesity (2008) 16, 938-944.Fully differentiated 3T3-L1 adipocytes are serum starved for 18 hours inDMEM containing 0.2% fatty acid free bovine serum albumin (BSA) and 0.1mM pyruvate. A stock of 5 mM test compound is prepared in 100% ethanoland then is diluted 1:100 in 2% fatty acid free BSA in DMEM (with 0.1 mMpyruvate), yielding a 50 μM solution of compound. Starvation media isremoved from cells and is replaced by the 50 μM compound solution inDMEM or Vehicle (0.1% ethanol, 0.2% fatty acid free BSA in DMEM with 0.1mM pyruvate). Test compound or Vehicle is incubated with cells for 48hours. Subsequently, RNA is purified from cells and reverse transcribedto cDNA. IL-10 message levels are then measured by quantitativereal-time PCR (Applied Biosystems Step-One) using gene-specificoligoneucleotide primers and fluorescently labeled probe. IL-10 levelsare normalized to the house-keeping gene GAPDH, which was measured usingthe same method. IL-10 levels in Compound of the Invention treatedsamples are expressed as a fold increase over IL-10 levels in Vehicletreated samples. (**p<0.005 by 2-tailed t-test). A sample graph showingthe data obtained by using one of the Compounds of the Inventiondescribed above in Example 4 is shown in FIG. 1.

Example 5 Effects of Compounds of the Invention in Fao Hepatoma Cells

Fao cells are serum starved for 16 hours followed by 2-hour incubationsat 37° C. with 5 mM-25 mM a Compound of the Invention according to themethod described in Yuan, M., et al., Science, 293, 1673-1677, 2001.Cells are then stimulated sequentially with 6.0 nM mTNFα for 20 min. and10 nM insulin for 5 min. Cells are chilled and solubilized and proteinsare then immunoprecipitated with anti-IR and detected by Westernblotting using anti-pY. Phosphorylation is quantified by densitometry.

Example 6 TNFα Release Assay in RAW 264.7 Macrophages

The purpose of this assay is to measure the ability of small moleculesto inhibit the secretion of TNFα in cultured macrophages stimulated withlipopolysaccharide (LPS). Treatment of macrophages with LPS activatesinflammatory cytokine pathways primarily through the TLR4-NFκB signalingaxis. Compounds of the Invention inhibit the transcriptional activationof NFκB and thus decrease the production and release of TNFα.Dexamethasone, a potent agonist of the glucocorticoid receptor is used apositive control for inhibition of TNFα release.

Day 1: Seed RAW 264.7 macrophages into 96 well culture plates. Removeculture media from RAW 264.7 cell growing in a 75 mm² tissue cultureflask (cells should be at ˜70% confluence) and add 10 ml of warmedcomplete growth media (DMEM+10% FBS+1× pen/step). The cells are scrapedinto suspension using a sterile plate scraper and homogenized bypipetting up and down with a 10 ml serological pipette. The cellconcentration is determined using a clinical hematoctyometer. Cells arethen diluted to 150,000 cells per ml into growth media. The dilutedcells are then transferred to a sterile reagent reservoir and 100 μl ofcell suspension is pipetted into each well of a 96 well culture plateusing a multichannel pipette (15,000 cells/well). Plates are thenincubated at 37° C. under normal tissue culture growth conditions (37°C., humidified CO₂ chamber).

Day 2: The test compound sample plate is prepared. Test compounds areprepared in growth media. Compounds are delivered to media from 1000×stocks in 100% DMSO (e.g. for a 10 μM final concentration of testcompound, deliver 2 μl of 10 mM test compound to 2 ml of media). Atleast 150 μl of 1× compound in media is added to 96 well sample plate.Note: the perimeter wells of the 96 well plate are not used to avoidedge effects. Twelve sample wells are prepared with media plus 0.1% DMSO(these samples will serve as the vehicle controls; LPS-stimulated andnon-stimulated. 10 μM dexamethasone is used as a positive control).Culture plates are then returned to the growth incubator for 2 hours.Cells are stimulated afterwards by adding 25 μl of 50 ng/ml LPS is addedto every well (except the 6 unstimulated vehicle control wells: finalconcentration of 10 ng/ml LPS. Plates are returned to growth incubatorfor 3 hours. Afterwards, 100 μl of media supernatant is removed andtransferred to a 96 well v-bottom sample plate. The media supernatantplate is centrifuged for 5 minutes at 1000 rpm in a swing-bucketcentrifuge, pelleting any cellular debris that may remain insupernatant. 80 μl of supernatant is removed from sample plate andtransferred to a fresh v-bottom 96 well plate. Cell viability ismeasured using Celltiter-glo kit. By measuring cell viability, a givencompound′s effects on TNFα secretion can determine whether effects aredue to cytotoxicity or to true inhibition of inflammatory signaling. Add100 μl of Celltiter-glo reagent to each well of the cell culture plateand afterwards measure the luminescence signal (CPS) of the plate usingthe Victor 5 plate reader (0.3 second read; 60 second plate shakingprior to read). Cell viability of a given compound at a givenconcentration is computed as follows:

Cell viability ═CPS Sample/(Average CPS unstimulated controls)*100

Use 20 μl of media supernatant per well for TNFα ELISA. FollowInvitrogen/Biosource manufacture′s protocol for the mouse TNFα ELISA.Chromogen development is typically conducted for 20-30 minutes asdescribed in the manufacturer's protocol. After addition of stopsolution, measure OD 450 nm using the Victor 5 plate reader (0.1second/well scan). Determine the TNFα secretion percent of control. Thefollowing formula is used to determine the TNFα secretion percent ofcontrol:

$\frac{\begin{matrix}{{100 \times \left( {{OD}\mspace{14mu} 45\mspace{14mu} {nm}\mspace{14mu} {Sample}\mspace{14mu} X} \right)} -} \\\left( {{Average}\mspace{14mu} {OD}\mspace{11mu} 450\mspace{14mu} {nm}\mspace{14mu} {unstimulated}\mspace{14mu} {vehicle}\mspace{14mu} {controls}} \right)\end{matrix}}{\begin{matrix}{\left( {{Average}\mspace{14mu} {OD}\mspace{14mu} 450\mspace{14mu} {nm}\mspace{14mu} {LPS}\mspace{14mu} {stimulated}\mspace{14mu} {vehicle}\mspace{14mu} {controls}} \right) -} \\\left( {{Average}\mspace{14mu} {OD}\mspace{14mu} 450\mspace{14mu} {nm}\mspace{14mu} {unstimulated}\mspace{14mu} {vehicle}\mspace{14mu} {controls}} \right)\end{matrix}}$

For each test compound, TNFα secretion percent of control can be plottedas a function of compound concentration using a four parameterdose-response curve fit equation (XLFIT Model #205):

fit=(A+((B−A)/(1+((C/x)̂D))))

inv=(C/((((B−A)/(y−A))-1)̂(1/D)))

res=(y−fit)

For compounds which cause greater than 50% inhibition of TNFα secretion,determine the IC₅₀ (concentration of compound which causes 50%inhibition of TNFα secretion). A sample graph showing the data obtainedby using one of the Compounds of the Invention in the proceduredescribed above in Example 6 is shown in FIG. 2.

As seen in FIG. 2, salicylate alone, fatty acid alone, and the simplecombination of salicylate and fatty acid administered together do notappreciably inhibit the production of TNFα. In contrast the fatty acidacetylated salicylate significantly inhibits the production of TNFα.This demonstrates that the fatty acid acetylated salicylate is thespecies responsible for the inhibition of TNFα production and not eitherof the individual components alone or in simple combination.

A sample table showing the data obtained by using additional Compoundsof the Invention in the procedure described above in Example 6 is shownin Table 1, below:

TABLE 1 Compound TNF Secrection, Number IC₅₀ uM Ia-1 69.2 III-1 145.6Ic-1 NT Ic-10 15.0 5ASA >100 Ic-11 NT DHA >100 III-6 65.3 I-1 24.4%Inhibition at 6.2 uM

Example 7 In Vivo Effects of Compounds of the Invention in anLPS-Challenge TNFα Mouse Model

To measure the effects of compounds on TNFα secretion in vivo, MaleSwiss Webster mice (n=10 animals per group) are dosed by oral gavagewith each test compound. All compounds are formulated in an aqueoussolution of 0.5% carboxymethylcellulose and 0.05% TWEEN-80 (Vehicle).One hour after compound dosing, animals are treated with 0.2 mg/kg LPS(lipopolysaccharide) by intraperitoneal (IP) injection. Ninety minutesafter LPS challenge, mice are anesthetized and bled by cardiac punctureinto serum separator tubes (with sodium heparin). Bleeds are allowed toclot at room temperature for 2 hours, and tubes are then spun for 20minutes at 2000×g. Serum is harvested from tubes (100-150 μl per animal)and frozen at −70° C. TNFα serum levels are measured using commerciallyavailable TNFα ELISA kits. (*p<0.05 using a 2-tailed t-test). A samplegraph showing the data obtained by using some of the Compounds of theInvention in the procedure described above in Example 7 is shown in FIG.3.

Example 8 Effects of Compounds of the Invention on NFκB Levels in RAW264.7 Macrophages

RAW 264.7 cells transfected with an NFκB-driven luciferase reporter areplated in 96 well plates. Cells are treated with Vehicle (0.1% ethanol)or test compounds for 2 hours. As a positive control for inhibition ofNFκB signaling, 6 wells are treated with 10 μM dexamethasone. Cells arethen challenged with 200 ng/ml LPS for 3 hours in the presence of testcompounds. A subset of wells treated with vehicle should remainunstimulated with LPS to determine the floor signal of the assay. NFκBdriven luciferase activity is developed by addition of BriteLiteluciferase kit (Perkin-Elmer) and measured using a Victor V platereader. NFκB activity (luciferase activity) for each treatment wasnormalized to Vehicle wells treated with LPS (% NFκB Response).AlamarBlue was used to monitor cell viability to ensure that inhibitionof luciferase signal was not a result of compound cytotoxicity.

A sample table showing the data obtained by using additional Compoundsof the Invention in the procedure described above in Example 8 is shownin Table 2, below:

TABLE 2 Compound NFκB Inhibitory Number Activity, IC₅₀ μM Ia-1 − III-1++++  3 +++ Ic-1 − Ic-10 ++++ Ic-11 − III-6 ++ I-1 ++++  9 +++ 10 ++ 11+++ 12 +++ 13 ++++ 14 ++++ 15 +++ 16 − 17 ++ 18 − 19 − 20 − 21 − 22 +++23 − 24 ++ 5-ASA − DHA − DHA + SA − SA − A − indicates that the compoundshowed no inhibitory activity. A + indicates that the compound showedinhibitory activity. A greater number of +'s indicates a higher level ofinhibitory activity.

Compounds

The following non-limiting compound examples serve to illustrate furtherembodiments of the Compounds of the Invention. It is to be furtherunderstood that any embodiments listed in the Examples section areembodiments of the Compounds of the Invention and, as such, are suitablefor use in the methods and compositions described above.

Example 9 Preparation of2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)benzoicacid (Ia-1)

To a mixture of DHA (6.0 g, 18.3 mmol) in dichloroethane (30 mL) and DMF(0.05 mL) was slowly added oxalyl chloride (5.0 mL, 56.9 mmol). Thereaction mixture was stirred (RT, 2 h) and concentrated under reducedpressure to obtain DHA-Cl as a yellow liquid. To a mixture of salicylicacid (3.78 g, 27.4 mmol) and NEt₃ (3.80 mL, 27.5 mmol) in dichloroethane(35 mL) at 0° C. was slowly added the DHA-Cl in dichloroethane (35 mL).The reaction mixture was stirred (RT, 16 h), washed with 1N HCl andbrine, dried over MgSO₄, filtered and concentrated under reducedpressure. The crude material was purified by silica chromatography(PE-EtOAc, 19:1) to afford2-(docosa-4,7,10,13,16,19-hexaenoyloxy)benzoic acid (5.83 g, 71%) as alight yellow oil. Mass calculated for C₂₉H₃₆O₄=448.59. found:[M−H]⁺=447.7.

Example 10 Preparation of5-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-2-hydroxybenzoicacid (III-1)

To a solution of saturated HCl in CH₃OH (20 mL) at RT was slowly added5-amino-2-hydroxybenzoic acid (2 g, 13.06 mmol). The resulting mixturewas stirred at (RT, 16 h) and then heated (reflux, 24 h). The mixturewas cooled and the solvent was removed under reduced pressure. Theresidue was diluted with EtOAc (50 mL) and washed with saturated aqueousNaHCO₃. The organic solution was dried over MgSO₄, filtered,concentrated under reduced pressure to afford methyl5-amino-2-hydroxybenzoate as a pale yellow solid (1.72 g, 78.5%). Masscalculated for C₈H₉NO₃=167.16. found: [M+H]⁺=168.2.

To a mixture of methyl 5-amino-2-hydroxybenzoate (52.9 mg, 0.317 mmol),DHA(100 mg, 0.305 mmol) and Et₃N (61.7 mg, 0.61 mmol) in CH₃CN (2 mL)was added HATU (120 mg, 0.260 mmol). The mixture was stirred (RT, 4.5h). The solvent was removed under reduced pressure and the residue wasextracted with EtOAc (4×20 mL). The combined organic layer was washedwith 1N aq. HCl, water, 5% NaHCO₃, water, and dried over MgSO₄. Thesolvent was removed under reduced pressure. The crude product waspurified by silica chromatography (EtOAc:PE, 1:10 to 2:3) to affordmethyl 5-docosa-4,7,10,13,16,19-hexaenamido-2-hydroxybenzoate (3) as alight yellow oil (104.5 mg, 72.1%). Mass calculated forC₃₀H₃₉NO₄=477.63. found: [M+H]⁺=478.5.

A mixture of methyl5-docosa-4,7,10,13,16,19-hexaenamido-2-hydroxybenzoate (0.1 g, 0.2 mmol)in 2N NaOH (5 mL) and CH₃OH (2.5 mL) was stirred (50° C., 24 h). Themixture was cooled and acidified to pH 1 with 2N aq. HCl, then extractedwith EtOAc (3×10 mL). The organic layer was washed with brine, driedover MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica chromatography (CH₂Cl₂-EtOAc, 20:1 to1:1) to afford 5-docosa-4,7,10,13,16,19-hexaenamido-2-hydroxybenzoicacid as a white solid (90.4 mg, yield: 90%). Mass calculated forC₂₉H₃₇NO₄=463.61. found: [M+H]⁺=464.3.

Example 11 Preparation of3-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropyl2-acetoxybenzoate (Ic-1)

To a mixture of 3-aminopropan-1-ol (5.0 g, 67 mmol), Na₂CO₃ (8.8 g, 83mmol) in THF (40 mL) and H₂O (130 mL) at 0° C. was added Cbz-Cl (14.8 g,87 mmol). The reaction mixture was stirred (RT, 1 h). Water (500 mL) andCH₂Cl₂ (500 mL) were added, and the layers were separated. The organiclayer was dried over MgSO₄ and concentrated under reduced pressure. Theresidue was purified by silica chromatography (PE:EA, 5:1) to affordbenzyl 3-hydroxypropylcarbamate as a white solid (12.6 g, 90.5%).

To a solution of 2-acetoxybenzoic acid (2.0 g, 11.1 mmol) andtriethylamine (1.8 mL, 11.1 mmol) in CH₂Cl₂ (40 mL) at 0° C. was slowlyadded ClCO₂Et (1.1 mL, 167 mmol). The reaction mixture was stirred (0°C., 2 h) and filtered. The filtrate was added to a solution of benzyl3-hydroxypropylcarbamate (2.1 g, 10.0 mmol) and triethylamine (15 mL) inCH₂Cl₂ (40 mL). The reaction mixture was stirred (RT, 4 h) and quenchedwith H₂O (50 mL). The organic layer was washed with 1 M HCl, saturatedNa₂CO₃ (30 mL) and H₂O (50 mL). The organic solution was dried overMgSO₄ and concentrated under reduced pressure. The residue was purifiedby silica chromatography, (PE-EtOAc, 5:1) to afford3-(benzyloxycarbonylamino)propyl 2-acetoxybenzoate (2.0 g, 54%) as acolorless oil. Mass calculated for C₂₀H₂₁NO6₄=371.38. found:[M+H]⁺=372.3.

A mixture of 3-(benzyloxycarbonylamino)propyl 2-acetoxybenzoate (2.0 g,5.4 mmol), 10% Pd/C (0.2 g) and CH₃OH (50 mL) was stirred under a H₂atmosphere (RT, 16 h). The mixture was filtered and concentrated underreduced pressure to afford a colorless oil. Purification by silicachromatography afforded 3-aminopropyl 2-acetoxybenzoate as a colorlessoil. Mass calculated for C₁₂H₁₅NO₄=237.25. found: [M+H]⁺=238.3.

To a solution of DHA (500 mg, 1.52 mmol) in ClCH₂CH₂Cl (10 mL) and onedrop of DMF at 0° C. was slowly added oxalyl chloride (0.3 mL, 3.42mmol). The reaction mixture was stirred (RT, 2 h) and concentrated underreduced pressure. The residue was treated with toluene (5 mL) and thesolvent was removed under reduced pressure to obtain the DHA acidchloride as a yellow liquid. To a solution of 3-aminopropyl2-acetoxybenzoate (360 mg, 1.52 mmol) and NEt₃ (0.36 g, 3.56 mmol) inClCH₂CH₂Cl (10 mL) at 0° C. was added a solution of DHA-acid chloride inClCH₂CH₂Cl. The reaction mixture was stirred (0° C., 2 h, then warmed toRT, 12 h). Purification by silica chromatography afforded3-docosa-4,7,10,13,16,19-hexaenamidopropyl 2-acetoxybenzoate. Masscalculated for C₃₄H₄₅NO₅=547.72. found: [M+H]⁺=548.3.

Example 12 Preparation ofN-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxybenzamide(Ic-10)

Ethylenediamine (1.0 g, 16.7 mmol) is dissolved in water (3.0 mL)containing bromoaresal green as an indicator. Methane sulfonic acid (2.8g, 31 mmol) in water (3.0 ml) was added until a blue to pale yellowcolor transition is just achieved. The solution was diluted with ethanol(8.0 mL) and vigorously stirred. To the mixture was added the solutionof Cbz-Cl (2.8 g, 16.7 mmol) in dimethoxyethane (4 mL) and 50% w/vaqueous AcOK (10 mL) at 20° C. simultaneously to maintain the paleyellow-green color of the indicator. After the additions are completethe mixture was stirred (RT, 1 h) and concentrated at low temperatureunder vacuum to removed the volatiles. The residue was shaken with water(20 mL) and filtered. The filtrate was then washed with toluene (3×50mL), basified with excess 40% aqueous NaOH and extracted with toluene(3×50 mL). The organic layer was washed with brine (50 mL), dried overNa₂SO₄ and evaporated to give benzyl 2-aminoethylcarbamate as an oil(1.65 g, 51%). Mass calculated for C₁₀H₁₄N₂O₂=194.23. found:[M−H]⁺=193.3.

To a mixture of benzyl 2-aminoethylcarbamate (1.65 g, 8.5 mmol),imidazole (0.58 g, 8.5 mmol), salicylic acid (1.73 g, 8.5 mmol) in ethylacetate (30 mL) was added a solution of DCC (1.75 g, 8.5 mmol) in ethylacetate (50 mL). The mixture was stirred (RT, 16 h) and filtered. Thesolution was concentrated under reduced pressure and the crude productwas purified by silica chromatography (EtOAc:PE, 0-50%) to afford benzyl2-(2-hydroxybenzamido)ethylcarbamate as a white solid (1.84 g, 66%).Mass calculated for C₁₇H₁₈N₂O₄=314.34. found: [M+H]⁺=315.2.

A mixture of benzyl 2-(2-hydroxybenzamido)ethylcarbamate (1.84 g, 5.86mmol) and Pd/C (0.18 g) in MeOH (30 mL) was stirred under a H₂atmosphere (16 h). The mixture was filtered and concentrated underreduced pressure. The crude product was purified by silicachromatography (EtOAc-MeOH-NH₃OH (5:1:0.01) to affordN-2-(aminoethyl)-2-hydroxybenzamide as a white powder (0.68 g, 65%).Mass calculated for C₀H₁₂N₂O₂=180.20; found: [M+H]⁺=181.2.

To a mixture of N-2-(aminoethyl)-2-hydroxybenzamide (58 mg, 0.32 mmol),DHA (100 mg, 0.3 mmol) and Et₃N (0.1 ml, 0.7 mmol) in CH₃CN (2 mL) wasadded HATU (115 mg, 0.3 mmol). The mixture was stirred (RT, 24 h) andconcentrated under reduced pressure. The residue was treated with brine(15 mL) and extracted with EtOAc (3×30 mL). The combined organic layerswere washed with 1M HCl, brine, 5% NaHCO₃ and brine. The organicsolution was dried over MgSO₄ and concentrated under reduced pressure.The crude product was purified by silica chromatography (EtOAc:PE, 1:1)to affordN-(2-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxybenzamide (94 mg,64%) as light yellow oil. Mass calculated for C₃₁H₄₂N₂O₃=490.68. found:[M+H]⁺=491.4.

Example 13 Preparation of(4Z,7Z,10Z,13Z,16Z,19Z)-1-(4-(2-hydroxybenzoyl)piperazin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one(Ic-11)

To a mixture of tert-butylpiperazine-1-carboxylate (0.57 g, 3.05 mmol),DHA (1 g, 3.05 mmol) and Et₃N (0.61 g, 6.1 mmol) in CH₃CN (20 mL) wasadded HATU (1.16 g, 3.05 mmol). The mixture was stirred (RT, 16 h). Thesolvent was removed under reduced pressure and the residue was extractedwith EtOAc (4×30 mL). The combined organic layers were washedsuccessively with 1N aqueous HCl, water, 5% NaHCO₃ and water, and driedover MgSO₄. The solvent was removed under reduced pressure and the crudeproduct was purified by silica chromatography (EA-PE, 1:10 to 1:1) toafford tert-butyl4-docosa-4,7,10,13,16,19-hexaenoylpiperazine-1-carboxylate (1.5 g, 99%)as a colorless oil. Mass calculated for C₃₁H₄₈N₂O₃=496.72. found:[M+H]⁺=497.6.

To a mixture of tert-butyl4-docosa-4,7,10,13,16,19-hexaenoylpiperazine-1-carboxylate (1.5 g, 3mmol) in CH₂Cl₂ (20 mL) at 0° C. was added CF₃CO₂H (7 mL, 91 mmol). Themixture solution was stirred (0° C., 2 h) and then 10% Na₂CO₃ was addedto adjust pH=10. The mixture was extracted with CH₂Cl₂ (3×30 mL). Thecombined organic layers were dried over MgSO₄, filtered and concentratedunder reduced pressure. The crude product was purified by silicachromatography (CH₂Cl₂:CH₃OH, 20:1) to afford1-(piperazin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one (1.17 g, 97.5%) asa colorless oil. Mass calculated for C₂₆H₄₀N₂O=396.61. found:[M+H]⁺=396.7, 398.2.

To a mixture of 1-(piperazin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one(1.17 g, 2.95 mmol), salicylic acid (0.61 g, 4.43 mmol) and Et₃N (0.89g, 8.85 mmol) in CH₃CN (10 mL) was added HATU (1.68 g, 4.43 mmol). Themixture was stirred (RT, 16 h). The solvent was removed under reducedpressure and the residue was extracted with EtOAc (4×50 mL). Thecombined organic layers were washed successively with 1N aqueous HCl,water, 5% NaHCO₃ and water, and dried over MgSO₄. The solvent wasremoved under reduced pressure. Purification of the crude product byprep-HPLC afforded1-(4-(2-hydroxybenzoyl)piperazin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one(300 mg, 19.6%) as a light yellow oil. Mass calculated forC₃₃H₄₄N₂O₃=516.71. found: [M+H]⁺ 517.6.

Example 14 Preparation of5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanamido)-2-hydroxybenzoicacid (III-6)

A mixture of 2-(benzyloxycarbonylamino)-4-methylpentanoic acid (1 g, 3.8mmol), methyl 5-amino-2-hydroxybenzoate (0.66 g, 3.95 mmol) and Et₃N(0.76 g, 7.6 mmol) were dissolved in CH₃CN (10 mL) and HATU (1.503 g,3.95 mmol) was added. The mixture was stirred (RT, 16 h). The solventwas removed under reduced pressure. Brine (50 mL) was added to theresulting residue, and the mixture was extracted with EtOAc (3×50 mL).The combined organic layers were washed successively with 2N aq. HCl(3×50 mL), brine (50 mL), 5% NaHCO₃ (50 mL×3), brine (50 mL), dried overMgSO₄, filtered, and concentrated under reduced pressure. The crudematerial was purified by silica chromatography on (CH₂Cl₂) to givemethyl5-(2-(benzyloxycarbonylamino)-4-methylpentanamido)-2-hydroxybenzoate asa white solid (0.81 g, 51.8%).

The mixture of5-(2-(benzyloxycarbonylamino)-4-methylpentanamido)-2-hydroxybenzoate(0.81 g, 1.9 mmol) and 0.1 g Pd/C in MeOH (15 mL) was stirred under H₂(RT, 16 h). The mixture was filtered and the filtrate was concentratedunder reduced pressure. The crude product was purified by silicachromatography (MeOH/DCM, 0 to 5%)) to afford methyl5-(2-amino-4-methylpentanamido)-2-hydrozybenzoate as a white solid (0.53g, 90%). Mass calculated for C₁₄H₂₀N₂O₄=280.32. found: [M+H]⁺=281.2.

To a solution of methyl5-(2-amino-4-methylpentanamido)-2-hydrozybenzoate (85 mg, 0.30 mmol),DHA (100 mg, 0.30 mmol), Et₃N (0.1 ml 0.71 mmol) in CH₃CN (2 mL) wasadded HATU (114 mg, 0.30 mmol). The mixture was stirred (RT, 16 h) andthe solvent was removed under reduced pressure. The residue was dilutedwith brine (20 mL) and extracted with ethyl acetate (50 mL). Thecombined organic layer was washed with 1M HCl (20 mL), brine (20 mL), 5%aq. NaHCO₃ (20 mL) and brine (20 mL), dried over MgSO₄, and concentratedunder reduced pressure. The crude product was purified by silicachromatography (EtOAc/DCM, 0 to 10%) to afford methyl5-(2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanamido)-2-hydroxybenzoateas light yellow oil. (155 mg, 87%). Mass calculated forC₃₆H₅₀N₂O₅=590.79; found: [M+H]⁺=591.6.

To a solution of methyl5-(2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanamido)-2-hydroxybenzoate(155 mg, 0.26 mmol) in MeOH (3 mL) was added 2M NaOH (5 mL). The mixturewas heated (45-50° C., 16 h), and then cooled to RT. 2M HCl was addeddropwise to adjust pH=1. The mixture was then extracted by EA (3×20 mL).The combined organic layers were washed with brine, dried over MgSO₄ andconcentrated under reduced pressure. The crude product was purified bysilica chromatography (MeOH/DCM, 0-10%) to afford of5-(2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanamido)-2-hydroxybenzoicacid as light yellow oil (92 mg, 61%). Mass calculated forC₃₅H₄₈N₂O₅=576.77. found: [M+H]⁺=577.3.

Example 15 Preparation of ethyl2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)benzoate(I-1)

2-Amino-4-methylpentanoic acid (5.0 g 38.2 mmol) was slowly added tosat. HCl/MeOH (50 mL). The mixture was stirred (RT, 5 h) then heated toreflux (16 h). After the reaction, the solvent was removed under reducedpressure. The residue was diluted with water (50 mL), then NaHCO₃ wasadded to adjust pH=7. The mixture was then extracted with DCM (3×50 mL),the combined organic layers were dried over MgSO₄, concentrated underreduced pressure to afford methyl 2-amino-4-methylpentanoate as acolorless liquid (5.3 g, 96%). Mass calculated for C₇H₁₅NO₂=145.20.found: [M+H]⁺=145.9. The product was used in next step without furtherpurification.

To a solution of methyl 2-amino-4-methylpentanoate (250 mg, 1.6 mmol),DHA (510 mg, 1.5 mmol), Et₃N (0.42 mL, 3 mmol) in CH₃CN (20 mL) at RTwas added HATU (570 mg, 1.5 mmol). The mixture was stirred (RT, 16 h)and the solvent was removed under reduced pressure. The residue wasdiluted with brine and extracted with EtOAc. The organic layer waswashed with 1M HCl (50 mL), brine (50 mL), 5% NaHCO₃ (50 mL) and brine(50 mL). The organic solution was dried over MgSO₄ and concentratedunder reduced pressure. The crude product was purified by silicachromatography (EtOAc:PE, 0-25%) to afford methyl2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoate (0.61 g, 85%) asa light yellow oil. Mass calculated for C₂₉H₄₅NO₃=455.67. found:[M+H]⁺=456.2.

To a solution of methyl2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoate (610 mg, 1.34mmol) in MeOH (15 mL) was added 2 M NaOH (30 mL). The reaction mixturewas heated (50° C., 16 h), cooled (RT), and acidified with 2 M HCl topH=1. The mixture was extracted with EtOAc (3×50 mL). The combinedorganic layers were washed with brine, dried over MgSO₄, andconcentrated under reduced pressure. The crude product was purified bysilica chromatography, (MeOH:DCM, 0-10%) to afford2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoic acid (0.51 g,89%) as a light yellow solid. Mass calculated for C₂₈H₄₃NO₃=441.65.found: [M+H]⁺=442.1.

To a solution of 2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoicacid (50 mg, 0.11 mmol) and ethyl 2-hydroxybenzoate (19 mg, 0.11 mmol)in CH₃CN/THF (1:1, 0.5 mL) at −10° C. was added DCC (12 mg, 0.11 mmol)and DMAP (1 mg). The mixture was stirred (RT, 16 h), filtered andconcentrated under reduced pressure. The crude product was purified bysilica chromatography (EtOAc-PE, 0-20%) to afford ethyl2-(2-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)benzoate(40 mg, 67%) as colorless oil. Mass calculated for C₃₇H₅₁NO₅=589.80.found: [M+H]⁺=590.4.

Example 16 Preparation of1-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)ethyl2-acetoxybenzoate (9)

To a solution of compound 2-acetoxybenzoic acid (1.0 g, 5.5 mmol) in THF(30 mL) was added (COCl)₂ (0.8 ml, 9.1 mmol) at 0° C. The mixture washeated (reflux, 1.5 h) and concentrated under reduced pressure to afford2-(chlorocarbonyl)phenyl acetate.

To a mixture of 2,4,6-trimethyl-1,3,5-trioxane (245 mg, 1.85 mmol) andNaI (0.972 g, 6.48 mmol) in DCM (15 mL) was added a solution of2-(chlorocarbonyl)phenyl acetate in DCM (5 mL, 0° C.). The resultingmixture was allowed to stir (RT, 16 h). The mixture was filtrated andconcentrated under reduced pressure. The crude was purified by silicachromatography (EtOAc-PE, 0-10%) to afford 1-iodoethyl 2-acetoxybenzoate(0.75 g, 40%) as a light yellow oil.

To a solution of DHA (0.1 g, 0.3 mmol) in CH₃CN (1 mL) was added K₂CO₃(41.4 mg, 0.3 mmol) followed by Bu₄NBr (96.6 mg, 0.3 mmol). The mixturewas stirred (RT, 0.5 h) and cooled to 0° C. To it was added 1-iodoethyl2-acetoxybenzoate (0.1 g, 0.3 mmol) and the mixture was stirred (RT, 16h). The mixture was filtered, washed with brine and concentrated underreduced pressure. The crude was purified by silica chromatography(PE:EtOAc, 20:1-15:1) to afford1-(docosa-4,7,10,13,16,19-hexaenoyloxy)ethyl 2-acetoxybenzoate (85.3 mg,53.3%) as a light yellow oil. Mass calculated for C₃₃H₄₂O₆=534.68.found: [M+Na]⁺=557.2.

Example 17 Preparation of2-hydroxy-5-(9Z,12Z,15Z)-octadeca-9,12,15-trienamidobenzoic acid (III-7)

To a solution of (9Z,12Z,15Z)-octadeca-9,12,15-trienoic acid (1.66 g,5.98 mmol) and methyl 5-amino-2-hydroxybenzoate (1 g, 5.98 mmol) inmethylene chloride (100 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.16 g, 6.0mmol) and dimethylaminopyridine (100 mg). The mixture was stirred underN₂ (14 h) and then diluted with methylene chloride (100 mL) and washedsuccessively with 3N HCl, sat sodium bicarbonate solution and sat sodiumchloride solution. The organic layer was dried over anhydrous magnesiumsulfate, filtered and concentrated to give the corresponding amide, 2.0grams.

To the amide was added 2N NaOH (100 mL) and methanol (100 mL) and theresulting slurry was heated to 40° C. and after 12 hours an additional500 mg NaOH was added and the reaction stirred at 40° C. (12 hours). Thereaction mixture was cooled to room temperature, acidified with 3 N HCland extracted with ethyl acetate (300 mL). The organic phase was washedsuccessively with water and sat sodium chloride, dried over anhydrousmagnesium sulfate, filtered and was concentrated to give the product2-hydroxy-5-(9Z,12Z,15Z)-octadeca-9,12,15-trienamidobenzoic acid (1.5grams, 61%). Mass calculated for C₂₅H₃₅NO₄=413.55. found: [M−H]⁺=412.3.

Example 18 Preparation ofN-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxy-N-methylbenzamide(11)

To a solution of ethylenediamine (20 mL, 0.28 mol) in CHCl₃ (300 mL) at0° C. was slowly added a solution of Boc₂O (6.2 g, 0.028 mol) in CHCl₃(150 mL). The mixture was allowed to warm to room temperature. After 16h, the solution was filtered and washed with brine (6×100 ml) and water(100 ml). The organic solution was dried over MgSO₄, filtered andconcentrated under reduced pressure to afford tert-butyl2-aminoethylcarbamate (3.7 g, 78%) as a colorless oil.

To a solution of tert-butyl 2-aminoethylcarbamate (3.7 g, 22.3 mmol),benzaldehyde (2.36 g, 22.3 mmol) and MgSO₄ (1.33 g) in1,2-dicholoroethane (300 mL) and Et₃N (30.1 mL, 22.3 mmol) at RT wasadded NaHB(AcO)₃. The mixture was stirred (RT, 16 h) and filtered. Thesolution was washed with saturated NaHCO₃ (200 ml), dried over MgSO₄ andconcentrated under reduced pressure. The crude product was purified bychromatography on silica gel, eluting with MeOH-DCM (0-10%) to affordtert-butyl 2-(benzylamino)ethylcarbamate (1.4 g, 23%). Mass calculatedfor C₁₄H₂₂N₂O₂=250.34. found: [M+H]⁺=251.3.

To a mixture of tert-butyl 2-(benzylamino)ethylcarbamate (2.8 g, 11.2mmol) and 37% aqueous CH₂O (1.0 mL, 11.2 mmol) in 1,2-dicholoroethane(35 mL) at RT was added NaHB(AcO)₃ (3.7 g, 11.2 mmol). The mixture wasstirred (RT, 16 h), diluted with saturated aqueous NaHCO₃ (400 ml) andextracted with EA (3×300 ml). The organic layer was dried over MgSO₄ andconcentrated under reduced pressure to afford tert-butyl2-(benzyl(methyl)amino)ethylcarbamate (1.38 g, 46.8%). ¹HNMR (CDCl₃):δ7.25 (m, 5H, CH), 3.5 (s, 2H, CH₂), 3.3 (m, 2H, CH₂), 2.48 (m, 2H,CH₂), 2.2 (s, 3H, CH₃), 1.4 (s, 9H, CH₃).

A mixture of tert-butyl 2-(benzyl(methyl)amino)ethylcarbamate (1.20 g,4.54 mmol), 10% Pd/C (0.90 g) and MeOH (60 ml) was stirred under a H₂atmosphere (0.8 MPa, RT, 16 h). The mixture was filtered andconcentrated under reduced pressure. The crude material was purified bycolumn chromatography on silica gel, eluting with saturated NH₃ inMeOH-DCM (0-10%) to afford tert-butyl 2-(methylamino)ethylcarbamate as acolorless oil (0.54 g, 68.3%). ¹HNMR (CDCl₃): δ3.25 (m, 2H, CH₂), 2.7(m, 2H, CH₂), 2.49 (s, 3H, CH₃), 1.49 (s, 9H, CH₃).

To a mixture of tert-butyl 2-(methylamino)ethylcarbamate (0.348 g, 2mmol), 2-hydroxybenzoyl chloride (0.276 g, 2 mmol) and imidazole (0.136g, 2 mmol) in ethyl acetate (8 mL) at 0° C. was slowly added a solutionof DCC (0.412 g, 2 mmol) in ethyl acetate (2 mL). The mixture wasstirred (RT, 16 h), filtered and concentrated under reduced pressure.The crude material was purified by chromatography on silica gel, elutingwith ethyl acetate/petroleum ether (20-50%) to afford tert-butyl2-(2-hydroxy-N-methylbenzamido)ethylcarbamate (0.2 g, 34%) as acolorless oil. ¹HNMR (CDCl₃): δ7.5 (m, 2H, CH), 7.0 (d, 1H, CH), 6.8 (d,1H, CH), 3.7 (m, 2H, CH₂), 3.48 (m, 2H, CH₂), 3.2 (m, 3H, CH₃), 1.5 (s,9H, CH₃).

To a solution of tert-butyl2-(2-hydroxy-N-methylbenzamido)ethylcarbamate (0.2 g, 0.68 mmol) inCH₂Cl₂ (5 mL) at 0° C. was added trifluoroacetic acid (1.8 mL, 23.4mmol). The mixture was stirred (0° C., 16 h), concentrated under reducedpressure and neutralized with saturated NH₃ in CH₃OH. The mixture wasconcentrated under reduced pressure to affordN-(2-aminoethyl)-2-hydroxy-N-methylbenzamide as a colorless oil (0.5 g).This compound was used in the next step without further purification.Mass calculated for C₁₀H₁₄N₂O₂=194.23. found: [M+H]⁺=195.1.

To a mixture of the crude N-(2-aminoethyl)-2-hydroxy-N-methylbenzamide,DHA (100 mg, 0.3 mmol) and Et₃N (92.3 mg, 0.9 mmol) in CH₃CN (2 mL) atRT was added HATU (115.8 mg, 0.3 mmol). The mixture was stirred (RT, 16h) and concentrated under reduced pressure. The residue was diluted with50 mL ethyl acetate, washed with brine, 1N HCl, saturated NaHCO₃ andbrine. The organic layer was dried over MgSO₄, filtered and concentratedunder reduced pressure. The residue was purified by chromatography onsilica gel, eluting with CH₂Cl₂-EA (1:1) to affordN-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxy-N-methylbenzamide(40 mg, 26%) as a light yellow oil. Mass calculated forC₃₂H₄₄N₂O₃=504.70. found: [M+H]⁺=505.5.

Example 19 Preparation of2-hydroxy-N-(2-((4Z,7Z,10Z,13Z,16Z,19Z)—N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethyl)benzamide(12)

To a solution of tert-butyl 2-(methylamino)ethylcarbamate (0.82 g, 4.7mmol), prepared as previously described, DHA (1.55 g, 4.7 mmol) and Et₃N(1.32 mL, 9.4 mmol) in CH₃CN (40 mL) was added HATU (1.79 g, 4.7 mmol).The mixture was stirred (RT, 16 h) and concentrated under reducedpressure. The residue was diluted with brine (150 mL) and extracted withethyl acetate (2×150 mL). The combined organic layers were washed withsaturated NaHCO₃ (150 mL) and brine (150 mL), dried over MgSO₄, andconcentrated under reduced pressure. The crude product was purified bychromatography on silica gel, eluting with EA-PE (0-50%) to affordtert-butyl2-((4Z,7Z,10Z,13Z,16Z,19Z)—N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethylcarbamate(1.71 g, 77%) as a light yellow oil. Mass calculated forC₃₀H₄₈N₂O₃=484.71. found: [M+H]⁺=485.6.

To a solution of tert-butyl2-((4Z,7Z,10Z,13Z,16Z,19Z)—N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethylcarbamate(1.71 g, 3.5 mmol)) in dichloromethane (50 mL) at 0° C. was slowly addedTFA (17 mL). The mixture was stirred (0° C., 2 h) basified to pH 10 withsaturated aqueous Na₂CO₃ and extracted with EA (3×150 mL). The combinedorganic layers were dried over MgSO₄ and concentrated under reducedpressure to afford(4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-aminoethyl)-N-methyldocosa-4,7,10,13,16,19-hexaenamide(1.31 g, 97%) as a light yellow oil.

To a solution of(4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-aminoethyl)-N-methyldocosa-4,7,10,13,16,19-hexaenamide(104 mg, 0.27 mmol), 2-hydroxybenzoyl chloride (37 mg, 0.27 mmol) andimidazole (19 mg, 0.27 mmol) in EA (4 mL) at 0° C. was added dropwise asolution of DCC (0.57 g, 0.27 mmol) in EA (4 mL). The mixture wasstirred (RT, 16 h), filtered and concentrated under reduced pressure.The crude material was purified by chromatography on silica gel, elutingwith EA-PE (1:3) to afford2-hydroxy-N-(2-((4Z,7Z,10Z,13Z,16Z,19Z)—N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethyl)benzamide(100 mg, 73%) as a colorless oil. Mass calculated for C₃₂H₄₄N₂O₃=504.70.found: [M+H]⁺=505.5.

Example 20 Preparation ofN-(1-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropan-2-yl)-2-hydroxybenzamide(13)

To a solution of 1-aminopropan-2-ol (7.5 g, 0.1 mol) in THF-H₂O (1:1,150 mL) at RT was slowly added a solution of Boc₂O (21.8 g, 0.1 mol) inTHF (50 mL). The mixture was stirred (RT, 2 h) and concentrated underreduced pressure. The residue was extracted with EA (2×100 mL) and thecombined organic layers were washed with citric acid (0.5 M, 2×50 mL)and brine (100 mL). The organic solution was dried over MgSO₄, filteredand concentrated under reduced pressure to afford tert-butyl2-hydroxypropylcarbamate (15.3 g, 87.4%) as a colorless oil. Masscalculated for C₈H₁₇NO₃=175.23. found: [M+H]⁺=176.3.

To a solution of tert-butyl 2-hydroxypropylcarbamate (14.3 g, 81.7 mmol)and Et₃N (35.6 ml, 245.1 mmol) in CH₂Cl₂ (250 mL) at 0° C. was slowlyadded a solution of methanesulfonyl chloride (9.5 mL, 122.6 mmol) inCH₂Cl₂ (250 mL). The mixture was stirred at 0° C. for 2 h, diluted withCH₂Cl₂ (300 mL) and washed with water, 1 N HCl, 5% NaHCO₃ and brine. Theorganic layer was dried over MgSO₄ and concentrated under reducedpressure to afford1-(tert-butoxycarbonylamino)propan-2-ylmethanesulfonate (19.5 g, 94%) asa light yellow oil. Mass calculated for C₉H₁₉NO₅S=253.32. found:[M+H]⁺=254.2.

To a solution of 1-(tert-butoxycarbonylamino)propan-2-ylmethanesulfonate(10.0 g, 39.5 mmol) in DMF (100 mL) at RT was added NaN₃ (7.7 g, 118.5mmol). The reaction mixture was stirred at 85° C. for 24 h, cooled toRT, diluted with cold water (300 mL) and extracted with diethyl ether(3×300 mL). The combined organic layers were washed with saturatedNaHCO₃ (2×200 mL) and brine (200 mL), dried over MgSO₄, filtered andconcentrated under reduced pressure to afford tert-butyl2-azidopropylcarbamate (7.0 g, 88.6%) as a light yellow oil. ¹HNMR(CDCl₃): δ3.6 (m, 1H, CH), 3.25 (m, 1H, CH₂), 2.9 (m, 1H, CH₂), 1.49 (s,9H, CH₃), 1.2 (d, 3H, CH₃).

A mixture of afford tert-butyl 2-azidopropylcarbamate (7.0 g, 3.6 mmol)and Pd/C (0.7 g) in MeOH (250 mL) was stirred under a H₂ (1 atm)atmosphere (RT, 16 h). The mixture was filtered and concentrated underreduced pressure. The crude product was purified by chromatography onsilica gel, eluting with saturated NH₃ in MeOH-DCM (0-10%) to affordtert-butyl 2-aminopropylcarbamate (5.1 g, 83.7%) as a light yellow oil.¹HNMR (CDCl₃): δ4.9 (bs, 1H, NH), 3.15 (m, 1H, CH), 3.0 (m, 1H, CH₂),2.8 (m, 1H, CH₂), 1.7 (bs, 2H, NH₂), 1.5 (s, 9H, CH₃), 1.0 (d, 3H, CH₃).

To a solution of tert-butyl 2-aminopropylcarbamate (3.6 g, 20.6 mmol),2-hydroxybenzoic acid (2.79 g, 20.6 mmol) and imidazole (1.41 g, 20.6mmol) in EtOAc (100 mL) at 0° C. was slowly added a solution of DCC(4.26 g, 20.6 mmol) in EtOAc (50 mL). The reaction mixture was stirred(RT, 16 h), filtered and concentrated under reduced pressure. The crudeproduct was purified by silica chromatography, EtOAc/Petroleum ether(0-20%) to afford tert-butyl 2-(2-hydroxybenzamido)propylcarbamate (2.4g, 40%) as a white solid.

A mixture of tert-butyl 2-(2-hydroxybenzamido)propylcarbamate (2.4 g,8.16 mmol) in saturated HCl-MeOH (50 mL) was stirred (RT, 2 h) andconcentrated under reduced pressure to affordN-(1-aminopropan-2-yl)-2-hydroxybenzamide (1.8 g, 96%) as a white solid.Mass calculated for C₁₀H₁₄N₂O₂=194.23. found: [M+H]⁺=195.2.

To a solution of N-(1-aminopropan-2-yl)-2-hydroxybenzamide (1.7 g, 7.3mmol), DHA (2.0 g, 6.1 mmol) and Et₃N (3.1 mL, 21.9 mmol) in CH₃CN (50mL) at 0° C. was added HATU (2.77 g, 7.3 mmol). The mixture was allowedto warm to RT, stirred for 16 h and concentrated under reduced pressure.The residue was diluted with brine (150 mL) and extracted with EA (2×200mL). The combined organic layers were washed with 1 N HCl (2×150 mL),saturated NaHCO₃ (2×150 mL) and brine (150 mL), dried over MgSO₄,filtered and concentrated under reduced pressure. The residue waspurified by chromatography on silica gel, eluting with EA-PE (0-25%) toafford the crude product, which was further purified by Prep-HPLC toaffordN-(1-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropan-2-yl)-2-hydroxybenzamide(1.31 g, 42.6%) as a light yellow oil. Mass calculated forC₃₂H₄₄N₂O₃=504.70. found: [M+H]⁺=505.5.

Example 21 Preparation ofN-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropyl)-2-hydroxybenzamide(14)

To a solution of tert-butyl 2-aminopropylcarbamate (1.06 g, 6.09 mmol,prepared as previously described), DHA (2.0 g, 6.09 mmol) and Et₃N (1.7mL, 12.8 mmol) in CH₃CN (40 mL) at 0° C. was added HATU (2.31 g, 6.09mmol). The mixture was stirred (RT, 16 h) and concentrated under reducedpressure. The residue was diluted with brine (100 mL) and extracted withEA (2×100 mL). The combined organic layers were washed with saturatedNaHCO₃ (100 mL) and brine (100 mL), dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude product was purified bychromatography on silica gel, eluting with EA-PE (0-25%) to affordtert-butyl2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropylcarbamate(2.1 g, 70%) as a light yellow oil. Mass calculated forC₃₀H₄₈N₂O₃=484.71. found: [M+H]⁺=485.6.

To a solution of tert-butyl2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropylcarbamate(2.10 g, 4.34 mmol) in DCM (100 mL) at 0° C. was slowly added TFA (30mL). The mixture was stirred (0° C., 2 h), warmed to RT and stirred (16h). The mixture was basified to pH=10 with saturated aqueous Na₂CO₃ andextracted with EA (2×200 mL). The combined organic layers were driedover MgSO₄, filtered and concentrated under reduced pressure to afford(4Z,7Z,10Z,13Z,16Z,19Z)—N-(1-aminopropan-2-yl)docosa-4,7,10,13,16,19-hexaenamide(1.60 g, 98%) as a light yellow oil. Mass calculated forC₂₅H₄₀N₂O=384.6. found: [M+H]⁺=385.2.

To a solution of(4Z,7Z,10Z,13Z,16Z,19Z)—N-(1-aminopropan-2-yl)docosa-4,7,10,13,16,19-hexaenamide(1.60 g, 4.2 mmol), 2-hydroxybenzoic acid (0.57 g, 4.2 mmol) andimidazole (0.29 g, 4.2 mmol) in EA (40 mL) at 0° C. was added a solutionof DCC (0.87 g, 4.2 mmol) in EA (40 mL). The mixture was allowed to warmto RT, stirred (16 h) and filtered. The solvent was removed underreduced pressure and the crude product was purified by chromatography onsilica gel, eluting with EA-PE (0-50%) to affordN-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropyl)-2-hydroxybenzamide(1.07 g, 50.5%) as a light yellow oil. Mass calculated forC₃₂H₄₄N₂O₃=504.70. found: [M+H]⁺=505.5.

Example 22 Preparation ofN-(3-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidobutan-2-yl)-2-hydroxybenzamide(15)

To a solution of butane 2,3-diol (15 g, 0.166 mol) and Et₃N (57.7 mL,0.415 mol) in CH₂Cl₂ (150 mL) at 0° C. was slowly added a solution ofCH₃SO₂Cl (32.1 mL, 0.415 mol) in CH₂Cl₂ (75 mL). The mixture was stirredat 0° C. for 2 h and diluted with CH₂Cl₂. The mixture was washed withwater, 1 N HCl, 5% aqueous NaHCO₃ and brine. The organic layer was driedover MgSO₄, filtered and concentrated under reduced pressure to affordbutane-2,3-diyl dimethanesulfonate (40 g, 98%) as a light yellow oil.¹HNMR (CDCl₃): δ4.9 (m, 2H, CH), 3.05 (s, 6H, CH₃), 1.4 (m, 6H, CH₃).

To a solution of butane-2,3-diyl dimethanesulfonate (15.0 g, 63.7 mmol)in DMF (150 mL) at RT was added NaN₃ (19.6 g, 301.5 mmol). The reactionmixture was stirred at 85° C. for 24 h, cooled to RT, diluted with coldwater (100 mL) and extracted with diethyl ether (4×100 mL). The combinedorganic layers were washed with saturated NaHCO₃ (2×100 mL) and brine(100 mL), dried over MgSO₄, filtered and concentrated under reducedpressure. The crude product was purified by flash chromatography onsilica gel, eluting with PE:EA (5:1) to afford 2,3-diazidobutane (6.10g, 68%) as a colorless oil.

A mixture of 2,3-diazidobutane (9.0 g, 64.3 mmol) and 10% Pd/C (0.90 g)in MeOH (300 mL) was stirred under a H₂ atmosphere (RT, 16 h). Themixture was filtered and concentrated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel, elutingwith saturated NH₃ in MeOH-DCM (0-20%) to afford butane-2,3-diamine (4.8g, 85%) as a yellow oil. ¹HNMR (CDCl₃): δ2.8 (m, 1H, CH), 2.6 (m, 1H,CH), 1.65 (s, 4H, NH₂), 1.0 (d, 6H, CH₃).

To a mixture of butane-2,3-diamine (4.8 g, 54.5 mmol) in water (50 mL)containing bromocresol green as indicator was slowly added a solution ofmethane sulfonic acid (10.46 g) in water (50 mL) until a blue to yellowcolor transition was observed. The mixture was diluted with ethanol (100mL) and to it was added a solution of Cbz-Cl (7.61 g, 45.5 mmol) in DME(50 mL) and aqueous AcOK (w/v=50%) to maintain the pale-green color. Thereaction mixture was stirred (RT, 1 h), concentrated under reducedpressure, treated with water and filtered. The solution was washed withtoluene, basified with 40% aqueous NaOH and extracted with toluene(4×100 mL). The combined organic layers were washed with brine, driedover MgSO₄, filtered and concentrated under reduced pressure to affordbenzyl 3-aminobutan-2-ylcarbamate (4.2 g, 35%) as a colorless oil. Masscalculated for C₁₂H₁₈N₂O₂=222.28. found: [M−H]⁺=221.2.

To a mixture of benzyl 3-aminobutan-2-ylcarbamate (5.3 g, 23.8 mmol),2-hydroxybenzoic acid (3.28 g, 23.8 mmol) and imidazole (1.62 g, 23.8mmol) in EtOAc (180 mL) at 0° C. was slowly added a solution of DCC(4.90 g, 23.8 mmol) in EtOAc (20 mL). The reaction mixture was stirred(RT, 16 h), filtered and concentrated under reduced pressure. The crudeproduct was purified by column chromatography on silica gel, elutingwith PE-EA (5:1) to afford benzyl3-(2-hydroxybenzamido)butan-2-ylcarbamate (3.2 g, 40%) as a colorlessoil. Mass calculated for C₁₉H₂₂N₂O₄=342.39. found: [M+H]⁺=343.2.

A mixture of benzyl 3-(2-hydroxybenzamido)butan-2-ylcarbamate (3.2 g,9.36 mmol) and 10% Pd/C (0.32 g) in MeOH (120 mL) was stirred under a H₂(1 atm) atmosphere (RT, 16 h). The mixture was filtered and concentratedunder reduced pressure. The crude product was purified by columnchromatography on silica gel, eluting with MeOH-DCM (0-20%) to affordN-(3-aminobutan-2-yl)-2-hydroxybenzamide (1.67 g, 86%) as a yellow oil.

To a solution of N-(3-aminobutan-2-yl)-2-hydroxybenzamide (1.52 g, 7.3mmol), DHA (2 g, 6.0 mmol) and Et₃N (1.21 g, 12.0 mmol) in CH₃CN (50 mL)at 0° C. was added HATU (2.37 g, 6.24 mmol). The mixture was stirred(RT, 16 h) and concentrated under reduced pressure. The residue wasdiluted with brine (50 mL) and extracted with EA (3×50 mL). The combinedorganic layers were washed with 1 N HCl (2×50 mL), saturated NaHCO₃(2×50 mL) and brine (50 mL), dried over MgSO₄, and concentrated underreduced pressure. The crude product was purified by chromatography onsilica gel, eluting with EA-PE (0-25%) to affordN-(3-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidobutan-2-yl)-2-hydroxybenzamide(1.08 g, 34.3%) as a light yellow oil. Mass calculated forC₃₃H₄₆N₂O₃=518.73. found: [M+H]⁺=519.6.

Example 23 Preparation of3-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidobenzoic acid(17)

To a solution of DHA (0.10 g, 0.3 mmol) in dichloromethane (3 mL) wasadded methyl 3-aminobenzoate (0.046 g, 0.3 mmol), EDCI (0.064 g, 0.3mmol) and dimethylaminopyridine (4 mg, 0.03 mmol). The reaction mixturewas stirred (RT, 2 h) and then partitioned between CH₂Cl₂ and water. Theaqueous layer was extracted with CH₂Cl₂, and the combined organicextracts were washed with 10% HCl, brine and dried over MgSO₄. The crudematerial was purified by silica chromatography (0-30% ethylacetate/pentane) to afford methyl3-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidobenzoate.Mass calculated for C₃₀₂H₃₉NO₃=461.64. found: [M+H]⁺=462.3. This wasthen dissolved in MeOH (10 mL) and 5 N NaOH (2 mL). The mixture wasstirred at reflux (4 h), and then concentrated. The aqueous solution wasacidified to pH 3 with HCl, and the product was extracted with ethylacetate. The organic layer was washed with water, brine and dried overMgSO₄. The crude product was purified by silica chromatography (0-30%ethyl acetate/pentane) to afford 0.066 g of3-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidobenzoic acidas an off-white solid. Mass calculated for C₂₉H₃₇NO₃=447.61. found:[M−H]⁺=446.2.

Example 24 Preparation of2-hydroxy-5-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidobenzoic acid(18)

To a solution of methyl 5-amino-2-hydroxybenzoate (0.27 g, 1.6 mmol) indichloromethane (10 mL) was added arachidonic acid (0.5 g, 1.6 mmol),EDCI (0.32 g, 1.7 mmol) and dimethylaminopyridine (0.020 g, 0.2 mmol).The reaction was stirred (RT, 2 h), and then partitioned between CH₂Cl₂and brine. The aqueous layer was extracted with CH₂Cl₂, and the combinedorganic layers were washed with 1 N HCl, water, saturated aqueous NaHCO₃and water, and then dried over MgSO₄. The crude product was purified bysilica chromatography (0-5% MeOH/CH₂Cl₂) to afford 0.6 g of methyl2-hydroxy-5-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidobenzoate as abrown oil. Mass calculated for C₂₈H₃₉NO₄=453.61. found: [M+H]⁺=454.3.

The methyl2-hydroxy-5-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidobenzoate wasthen dissolved in THF (15 mL) and 3 N NaOH (5 mL). The mixture washeated (60° C., 2 h) and then concentrated and acified to pH 3 with 2 NHCl. The product was extracted with ethyl acetate, and the combinedorganic extracts were washed with brine and dried over MgSO₄. The crudeproduct was purified by silica chromatography (0-15% MeOH/CH₂Cl₂) toafford 0.3 g of as2-hydroxy-5-(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenamidobenzoic acid anorange solid. Mass calculated for C₂₇H₃₇NO₄=439.59. found: [M−H]⁺=438.3.

Example 25 Preparation of5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoacetamido)-2-hydroxybenzoicacid (19)

To a solution of methyl 5-amino-2-hydroxybenzoate (1.5 g, 9.0 mmol) indichloromethane (50 mL) was added BOC-glysine (1.57 g, 9.0 mmol), EDCI(1.89 g, 9.9 mmol) and dimethylaminopyridine (0.11 g, 0.9 mmol). Thereaction was stirred (RT, 2.5 h), and then partitioned between CH₂Cl₂and brine. The aqueous layer was extracted with CH₂Cl₂ and the combinedorganic layers were washed with brine and dried over MgSO₄. The crudeproduct was purified by silica chromatography (0-5% MeOH/CH₂Cl₂) toafford 1.37 g of methyl5-(2-(tert-butoxycarbonylamino)acetamido)-2-hydroxybenzoate. Masscalculated for C₁₅H₂₀N₂O₆=324.33. found: [M+Na]⁺=347.2.

The methyl 5-(2-(tert-butoxycarbonylamino)acetamido)-2-hydroxybenzoate(1.3 g, 4.0 mmol) was dissolved in CH₂Cl₂ (15 mL) and TFA (8 mL). Thereaction was stirred (RT, 2.5 h) and then concentrated to afford methyl5-(2-aminoacetamido)-2-hydroxybenzoate as a clear oil. [M+H]⁺=225.1. Theoil was dissolved in CH₂Cl₂ (20 mL) and to this was added DHA (1.3 g,4.0 mmol), EDCI (0.84 g, 4.4 mmol) and triethylamine (2.0 g, 20.0 mmol).The reaction was stirred (RT, 4 h) and then partitioned between CH₂Cl₂and brine. The aqueous layer was extracted with CH₂Cl₂, and the combinedorganic layers were dried over MgSO₄. The crude material was purified bysilica chromatography (0-5% MeOH/CH₂Cl₂) to afford 0.9 g of methyl5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoacetamido)-2-hydroxybenzoateas a tan solid. Mass calculated for C₁₀H₁₂N₂O₄=534.69. found:[M+H]⁺=535.4.

The methyl5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoacetamido)-2-hydroxybenzoate(0.9 g, 1.7 mmol) was dissolved in THF (15 mL) and 1 N NaOH (8 mL). Thereaction was stirred (50° C., 5 h), and then acidified to pH 3 with 2 NHCl. The product was extracted with ethyl acetate, and the combinedorganic extracts were washed with water, brine and dried over MgSO₄. Thecrude material was purified by silica chromatography (0-5% MeOH/CH₂Cl₂)to afford 0.4 0 g of5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoacetamido)-2-hydroxybenzoicacid as a yellow solid. [M+H]+=521.3. Mass calculated forC₃₁H₄₀N₂O₅=520.66. found: [M−H]⁺=519.2.

Example 26 Preparation ofN-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxy-4-(trifluoromethyl)benzamide(21)

To a solution of 2-hydroxy-4-(trifluoromethyl)benzoic acid (0.5 g, 2.4mmol) in CH₂Cl₂ (8 mL0 was added oxalyl chloride (0.46 g, 3.6 mmol) and2 drops of DMF. The reaction was stirred (RT, 2 h) and thenconcentrated. The resulting residue was dissolved in CH₂Cl₂ (8 mL) andtert-butyl 2-aminoethylcarbamate (0.39 g, 2.4 mmol) anddiisopropylethylamine (0.41 g, 3.2 mmol) were added. The reaction wasstirred (RT, 16 h) and then partitioned between CH₂Cl₂ and brine. Theaqueous layer was extracted with CH₂Cl₂ and the combined organicextracts were dried over MgSO₄. The crude material was purified bysilica chromatography (0-10% MeOH/CH₂Cl₂) to afford 0.55 g of tert-butyl2-(2-hydroxy-4-(trifluoromethyl)benzamido)ethylcarbamate. Masscalculated for C₁₅H₁₉F₃N₂O₄=348.32; found: [M+Na]⁺=371.1. This was thendissolved in CH₂Cl₂ (10 mL) and TFA (4 mL). The reaction was stirred(RT, 3 h) and concentrated and dried to afford 0.7 g ofN-(2-aminoethyl)-2-hydroxy-4-(trifluoromethyl)benzamide as a clear oil.Mass calculated for C₁₀H₁₁F₃N₂O₂=248.20. found: [M+H]⁺=249.1.

The N-(2-aminoethyl)-2-hydroxy-4-(trifluoromethyl)benzamide (0.7 g, 1.5mmol) was dissolved in CH₂Cl₂ (10 mL) and to this was added DHA (0.48 g,1.5 mmol), HATU (0.67 g, 1.8 mmol) and triethylamine (0.59 g, 5.9 mmol).The reaction was stirred (RT, 16 h) and then partitioned between CH₂Cl₂and brine. The aqueous layer was extracted with CH₂Cl₂ and the combinedorganic extracts were dried over MgSO₄. The crude material was purifiedby silica chromatography (0-10% MeOH/CH₂Cl₂) to afford 0.28 g ofN-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxy-4-(trifluoromethyl)benzamideas a yellow oil. Mass calculated for C₃₂H₄₁F₃N₂O₃=558.67. found:[M+H]⁺=559.3.

Example 27 Preparation of ethyl2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-3-phenylpropanoyloxy)benzoate(22)

To a solution of ethyl 2-hydroxybenzoate (0.5 g, 3.0 mmol) in CH₂Cl₂ (8mL) was added 2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (0.8g, 3.0 mmol), EDCI (0.63 g, 3.3 mmol) and dimethylaminopyridine (0.037g, 0.3 mmol). The reaction was stirred (RT, 3 h) and then partitionedbetween CH₂Cl₂ and brine. The aqueous layer was extracted with CH₂Cl₂and the combined organic extracts were dried over MgSO₄. The crudematerial was purified by silica chromatography (0-10% MeOH/CH₂Cl₂) toafford 1.2 g of ethyl2-(2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)benzoate. Masscalculated for C₂₃₅H₂₇NO₆=413.46. found: [M+Na]⁺=437.1.

The ethyl 2-(2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)benzoate(1.2 g, 2.9 mmol) was dissolved in CH₂Cl₂ (10 mL) and TFA (4 mL). Thereaction was stirred (RT, 3 h) and then concentrated. The crude materialwas purified by silica chromatography (0-10% MeOH/CH₂Cl₂) to afford 0.63g of ethyl 2-(2-amino-3-phenylpropanoyloxy)benzoate. Mass calculated forC₁₈H₁₉NO₄=313.35. found: [M+H]⁺=314.1

Ethyl 2-(2-amino-3-phenylpropanoyloxy)benzoate (0.24 g, 0.8 mmol) andDHA (0.25 g, 0.8 mmol) were combined in CH₂Cl₂ (10 mL) and to this wasadded HATU (0.35 g, 0.9 mmol) and diisopropylethylamine (0.30 g, 2.3mmol). The reaction was stirred (RT, 3 h) and then partitioned betweenCH₂Cl₂ and brine. The aqueous layer was extracted with CH₂Cl₂ and thecombined organic extracts were dried over MgSO₄. The crude material waspurified by silica chromatography (0-10% MeOH/CH₂Cl₂) to afford ethyl2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-3-phenylpropanoyloxy)benzoateas a tan solid. Mass calculated for C₄₀H₄₉NO₅=623.82. found:[M+H]⁺=624.2.

Example 28 Preparation of5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-3-phenylpropanamido)-2-hydroxybenzoicacid (23)

5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenamido-3-phenylpropanamido)-2-hydroxybenzoicacid was prepared in a similar fashion as5-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanamido)-2-hydroxybenzoicacid, using the appropriate phenylalanine starting material. Masscalculated for C₃₈H₄₆N₂O₅=610.78. found: [M−H]⁺=609.3.

Example 29 Preparation of2-hydroxy-5-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidobenzoicacid (24)

2-Hydroxy-5-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidobenzoicacid was prepared in a similar fashion as5-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-2-hydroxybenzoicacid, using the appropriate EPA starting material. Mass calculated forC₂₇H₃₅NO₄=437.57. found: [M−H]⁺=436.2.

Example 30 Preparation ofN-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2′,4′-difluoro-4-hydroxybiphenyl-3-carboxamide(25)

N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2′,4′-difluoro-4-hydroxybiphenyl-3-carboxamidewas prepared in a similar fashion asN-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxybenzamide,using the appropriate 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acidstarting material. Mass calculated for C₃₇H₄₄F₂N₂O₃=602.75. found:[M+H]⁺=603.3.

Example 31 Preparation of2′,4′-difluoro-4-hydroxy-N-(2-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidoethyl)biphenyl-3-carboxamide(26)

2′,4′-Difluoro-4-hydroxy-N-(2-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidoethyl)biphenyl-3-carboxamidewas prepared in a similar fashion asN-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxybenzamide,using the appropriate 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acidand EPA starting materials. for C₃₅H₄₂F₂N₂O₃=576.72. found:[M+H]⁺=577.3.

Example 32 Preparation of ethyl4-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)-2′,4′-difluorobiphenyl-3-carboxylate(27)

The 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid (1.0 g, 4.0 mmol)was dissolved in ethanol (30 mL) and sulfuric acid (8 mL). The solutionwas stirred (80° C., 18 h) and then concentrated. The residue wasdissolved in ethyl acetate and washed with water, brine and dried overMgSO₄. Solvent evaporation afforded 1.0 g of ethyl2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate. Mass calculated forC₁₅H₁₂F₂O₃=278.25. found: [M+H]⁺=279.1.

The ethyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (0.3 g, 1.1mmol) was dissolved in CH₂Cl₂ (10 mL) and to this was added DHA (0.35 g,1.1 mmol), EDCI (0.23 g, 1.2 mmol) and dimethylaminopyridine (0.13 g,0.1 mmol). The reaction was stirred (RT, 3 h) and then partitionedbetween CH₂Cl₂ and brine. The aqueous layer was extracted with CH₂Cl₂and the combined organic extracts were dried over MgSO MgSO₄. The crudematerial was purified by silica chromatography (0-40% ethylacetate/pentane) to afford 0.1 g of ethyl4-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)-2′,4′-difluorobiphenyl-3-carboxylate.Mass calculated for C₃₇H₄₂F₂O₄=588.72. found: [M+H]⁺=589.3.

Example 33 Preparation of ethyl2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)-4-(trifluoromethyl)benzoate(28)

Ethyl2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)-4-(trifluoromethyl)benzoatewas prepared in a similar fashion as ethyl4-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)-2′,4′-difluorobiphenyl-3-carboxylate,using the appropriate 2-hydroxy-4-(trifluoromethyl)benzoic acid startingmaterial. Mass calculated for C₃₂H₃₉F₃O₄=544.64. found: [M+Na]⁺=567.3.

Example 34 Preparation of ethyl4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)-2′,4′-difluorobiphenyl-3-carboxylate(29)

Ethyl4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)-2′,4′-difluorobiphenyl-3-carboxylatewas prepared as described for ethyl2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)benzoate,using the appropriate 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acidstarting material. Mass calculated for C₄₃H₅₃F₂NO₅=701.88. found:[M+H]⁺=702.4.

Example 35 Preparation of ethyl2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)-4-(trifluoromethyl)benzoate(30)

Ethyl2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)-4-(trifluoromethyl)benzoatewas prepared as described for ethyl 2-(2(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido-4-methylpentanoyloxy)benzoate,using the appropriate 2-hydroxy-4-(trifluoromethyl)benzoic acid startingmaterial. Mass calculated for C₃₈H₅₀F₃NO₅=657.80. found: [M+H]⁺=658.4.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

1. A method of treating inflammation that is associated with a metabolicdisorder, wherein the metabolic disorder is selected from the groupconsisting of cardiovascular disease, arrhythmia, coronary arterydisease, and hypertriglyceridemia, comprising administering to a patientin need thereof an effective amount of a compound of Formula III:

or a pharmaceutically acceptable salt, enantiomer, or stereoisomerthereof, wherein W₁ is null and W₂ is independently null, O, orNH; - - - - - represents an optional bond that when present requiresthat Q is null; each a and c are independently H, CH₃, —OCH₃, —OCH₂CH₃,or C(O)OH; each b is H, CH₃, C(O)OH, or O—Z; each d is H or C(O)OH; eachn, o, p, and q is independently 0 or 1; each Z is H or

with the proviso that there is at least one

in the compound; each r is independently 2, 3, or 7; each s isindependently 3, 5, or 6; each t is independently 0 or 1; u is 0 or 1;with the proviso that when r is 7, s is 3; Q is null, C(O)CH₃, Z,

e is H or any one of the side chains of the naturally occurring aminoacids; W₃ is null, O, or —N(R)—; R is H or C₁-C₃ alkyl; and T is H,C(O)CH₃, or Z.
 2. The method of claim 1, wherein Q is H.
 3. The methodof claim 2, wherein the compound of Formula III is


4. The method of claim 3, wherein the compound of Formula III is


5. A method of treating inflammation that is associated with aneurodegenerative disorder selected from the group consisting ofHuntington's Disease, infectious meningitis, encephalomyelitis,Parkinson's disease, amyotrophic lateral sclerosis, and encephalitis,comprising administering to a patient in need thereof an effectiveamount of a compound of Formula III:

or a pharmaceutically acceptable salt, enantiomer, or stereoisomerthereof, wherein W₁ is null and W₂ is independently null, O, orNH; - - - - - represents an optional bond that when present requiresthat Q is null; each a and c are independently H, CH₃, —OCH₃, —OCH₂CH₃,or C(O)OH; each b is H, CH₃, C(O)OH, or O—Z; each d is H or C(O)OH; eachn, o, p, and q is independently 0 or 1; each Z is H or

with the proviso that there is at least one

in the compound; each r is independently 2, 3, or 7; each s isindependently 3, 5, or 6; each t is independently 0 or 1; u is 0 or 1;with the proviso that when r is 7, s is 3; Q is null, C(O)CH₃, Z,

e is H or any one of the side chains of the naturally occurring aminoacids; W₃ is null, O, or —N(R)—; R is H or C₁-C₃ alkyl; and T is H,C(O)CH₃, or Z.
 6. The method of claim 7, wherein Q is H.
 7. The methodof claim 17, wherein the compound of Formula III is


8. The method of claim 17, wherein the compound of Formula III is


9. A method of treating inflammation that is associated with a musclewasting disorder selected from the group consisting of dermatositis,inclusion body myositis, polymyositis, and cachexia, comprisingadministering to a patient in need thereof an effective amount of acompound of Formula III:

or a pharmaceutically acceptable salt, enantiomer, or stereoisomerthereof, wherein W₁ is null and W₂ is independently null, O, orNH; - - - - - represents an optional bond that when present requiresthat Q is null; each a and c are independently H, CH₃, —OCH₃, —OCH₂CH₃,or C(O)OH; each b is H, CH₃, C(O)OH, or O—Z; each d is H or C(O)OH; eachn, o, p, and q is independently 0 or 1; each Z is H or

with the proviso that there is at least one

in the compound; each r is independently 2, 3, or 7; each s isindependently 3, 5, or 6; each t is independently 0 or 1; u is 0 or 1;with the proviso that when r is 7, s is 3; Q is null, C(O)CH₃, Z,

e is H or any one of the side chains of the naturally occurring aminoacids; W₃ is null, O, or —N(R)—; R is H or C₁-C₃ alkyl; and T is H,C(O)CH₃, or Z.
 10. The method of claim 9, wherein Q is H.
 11. The methodof claim 10, wherein the compound of Formula III is


12. The method of claim 11, wherein the compound of Formula III is